Elastomeric functional biodegradable copolyester amides and copolyester urethanes

ABSTRACT

The present invention provides elastomeric copolyester amides, elastomeric copolyester urethanes, and methods for making the same. The polymers that are based on α-amino acids and possess suitable physical, chemical and biodegradation properties. The polymers are useful as carriers of drugs or other bioactive substances. The polymers can be linked, intermixed, or a combination thereof, to one or more drugs.

BACKGROUND OF THE INVENTION

[0001] While they potentially offer many advantages due to their“organic nature,” conventional poly(α-amino acids) possess manyundesirable physical, chemical and biodegradation properties. Forexample, the biological and material properties of conventionalpoly(α-amino acids) cannot be varied over a wide range. In addition, thesynthesis of many conventional poly(α-amino acids) is difficult andexpensive.

[0002] A considerable amount of attention has therefore been focused onreplacing the amide (peptide) linkage in the conventional poly(α-aminoacids) with a variety of non-amide bonds to provide novel polymericsystems that are based on α-amino acids. One class of α-amino acidderived polymers are polyisopeptides (alternatively known aspseudo-poly(amino acids)), which belong to the XY-type heterochainpolymers. Polyisopeptides are usually formed by linking trifunctionalα-amino acids in the backbone chains. However, relatively few attemptshave been made to synthesize polyisopeptides. For example, Sekiguchi etal. obtained poly-β-(α-alkyl-L-aspartate) by the ring-openingpolymerization of β-lactams. See, Rodriguez-Galan, A. et al., Makromol.Chem., Macromol. Symp., 6, 277 (1986) and Vives, J. et al., Makromol.Chem., Rapid Commun., 10(1):13 (1989). One major limiting feature ofpolyisopeptides is that structural modifications are limited solely tochemical variations at the N-acyl residue of the polyisopeptide. Thisnarrow range of chemical modification has resulted in an undesirablynarrow range of material properties of these polymers.

[0003] Another class of α-amino acid derived polymers are amino acidbased bioanalagous polymers (AABBPs), which belong to the XX-YYheterochain polymers. AABBPs are mainly obtained by the polycondensationof XX (one type of monomer having two X functional groups) and YY(another type of monomer having two Y functional groups). AABBPs are notpure polyamino acids or pseudo-polyamino acids because they includeresidues of other types of monomers (e.g., dicarboxylic acids anddiols).

[0004] One class of AABBPs are poly(ester ureas) (PEUs), which areprepared from bis-α-aminoacyl diol monomers. The first attempt to usebis-α-aminoacyl(phenylalanyl) diol for preparing bioabsorbable,semi-physiological polymers similar to poly(ester urea) was by Huang etal. Huang S. J., et al., J. Appl. Polym. Sci., 23(2): 429 (1979). Onlylow-molecular-weight PEUs, having limited material properties, could beprepared by this route.

[0005] Lipatova et al. have also synthesized semi-physiologicalpoly(ester urethane ureas) from bis-L-phenylalanyl diols, diols, anddiisocyanates. Lipatova T. E., et al., Dokl. Akad. Nauk SSSR, 251(2):368 (1980) and Gladyr I. I., et al. Vysokomol. Soed., 31B(3): 196(1989). However, no information on the synthesis of the startingmaterial (e.g., α-diamino diesters) was given.

[0006] Yoneyama et al. reported on the synthesis ofhigh-molecular-weight semi-physiological PEUs by the interaction of freeα-diamino-diesters with non-physiological diisocyanates. Yoneyama M., etal., Polym. Prepr. Jpn., 43(1): 177 (1994). Contrary to Huang et al.(Huang S. J., et al., J. Appl. Polym. Sci., 23(2): 429 (1979)),high-molecular-weight PEUs were obtained in some cases. In view of thispreliminary data, there remains an ongoing need for novel polymers basedon α-amino acids that possess a wide range of physical, chemical andbiodegradation properties.

SUMMARY OF THE INVENTION

[0007] The present invention provides polymers that are based on α-aminoacids. In contrast to conventional poly(α-amino acids), the polymers ofthe present invention (e.g., elastomeric functional copolyester amidesand copolyester urethanes) possess advantageous physical, chemical andbiodegradation properties. For example, the polymers of the presentinvention possess suitable biodegradation (weight loss percent)properties under varying conditions, (see, Table III). The hydrolysis ofthe polymers can be catalyzed by hydrolases (e.g., trypsin,a-chymotrypsin, lipase, etc.). As such, the polymers can be used ascarriers for covalent immobilization (attachment) of various drugs andother bioactive substances. In addition, the enzyme catalyzedbiodegradation rates of the polymer of the present invention can bechanged by varying the polymer composition (e.g., l/p ratio) and/or thenature of the functional groups (e.g., dicarboxylic acids, diols, orα-amino acids).

[0008] The present invention provides a polymer of formula (VII):

[0009] wherein

[0010] m is about 0.1 to about 0.9;

[0011] p is about 0.9 to about 0.1;

[0012] n is about 50 to about 150;

[0013] each R¹ is independently (C₂-C₂₀)alkylene;

[0014] each R² is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl;

[0015] each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; and

[0016] each R⁴ is independently (C₂-C₂₀)alkylene; comprising one or moresubunits of the formula (1):

[0017] and one or more subunits of the formula (II):

[0018] wherein

[0019] the combined number of subunits (I) and (II) is about 50 to about150.

[0020] Specifically, each R¹ can independently be (CH₂)₄, (CH₂)₈, or(CH₂)₁₂; R² can independently be hydrogen or benzyl; each R³ canindependently be iso-butyl or benzyl; and R⁴ can independently be(CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂)₁₂.

[0021] The present invention also provides a polymer of formula (VII):

[0022] wherein

[0023] m is about 0.1 to about 0.9;

[0024] p is about 0.9 to about 0.1;

[0025] n is about 50 to about 150;

[0026] each R¹ is independently (C₂-C₂₀)alkylene;

[0027] each R² is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl;

[0028] each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; and

[0029] each R⁴ is independently (C₂-C₂₀)alkylene.

[0030] Specifically, each R¹ can independently be (CH₂)₄, (CH₂)₈, or(CH₂)₁₂; each R² can independently be hydrogen or benzyl; each R³ canindependently be iso-butyl or benzyl; each R⁴ can independently be(CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂)₁₂; p/(P+m) can be about 0.9 to about0.1; and m/(p+m) can be about 0.1 to about 0.9.

[0031] The present invention also provides a polymer of formula (VII)formed from an amount of one or more compounds of formula (III):

[0032] wherein

[0033] each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; and

[0034] R⁴ is independently (C₂-C₂₀)alkylene; or a suitable salt thereof;and an amount of one or more compounds of formula (Iv):

[0035] wherein

[0036] R² is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; or asuitable salt thereof; and

[0037] an amount of one or more compounds of formula (V):

[0038] wherein

[0039] R¹ is independently (C₂-C₂₀)alkylene; and

[0040] each R⁵ is independently (C₆-C₁₀)aryl, optionally substitutedwith one or more nitro, cyano, halo, trifluoromethyl, ortrifluoromethoxy.

[0041] Specifically, R¹ can independently be (CH₂)₄, (CH₂)₈, or (CH₂)₁₂;R² can independently be hydrogen or benzyl; each R³ can independently beisobutyl or benzyl; R⁴ can independently be (CH₂)₄, (CH₂)₆, (CH₂)₈, or(CH₂)₁₂; each R⁵ can independently be p-nitrophenyl; the compound offormula (III) can be the di-p-tolunesulfonic acid salt of abis-(L-α-amino acid)-α,ω-alkylene diester; the compound of formula (IV)can be the di-p-tolunesulfonic acid salt of L-lysine benzyl ester, andthe compound of formula (V) can be di-p-nitrophenyl adipate,di-p-nitrophenyl sebacinate, or di-p-nitrophenyl dodecyldicarboxylate.

[0042] The present invention also provides a method for preparing apolymer of formula (VII):

[0043] wherein

[0044] m is about 0.1 to about 0.9;

[0045] p is about 0.9 to about 0.1;

[0046] n is about 50 to about 150;

[0047] each R¹ is independently (C₂-C₂₀)alkylene;

[0048] each R² is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl;

[0049] each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; and

[0050] each R⁴ is independently (C₂-C₂₀)alkylene;

[0051] comprising contacting an amount of one or more compounds offormula (III):

[0052] or a suitable salt thereof; and

[0053] an amount of one or more compounds of formula (IV):

[0054] or a suitable salt thereof; and

[0055] an amount of one or more compounds of formula (V):

[0056] wherein

[0057] each R⁵ is independently (C₆-C₁₀)aryl optionally substituted withone or more nitro, cyano, halo, trifluoromethyl, or trifluoromethoxy;

[0058] under suitable conditions to provide the polymer of formula(VII).

[0059] Specifically, each R¹ can independently be (CH₂)₄, (CH₂)₈, or(CH₂)₁₂; each R² can independently be hydrogen or benzyl; each R³ canindependently be iso-butyl or benzyl; each R⁴ can independently be(CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂)₁₂; each R⁵ can be p-nitrophenyl; thecompound of formula (III) can be the di-p-tolunesulfonic acid salt of abis-(L-α-amino acid)-α,ω-alkylene diester; the compound of formula (IV)can be the di-p-tolunesulfonic acid salt of L-lysine benzyl ester, thecompound of formula (V) can be di-p-nitrophenyl adipate,di-p-nitrophenyl sebacinate, or di-p-nitrophenyl dodecyldicarboxylate;p/(p+m) can be about 0.9 to about 0.1; and m/(p+m) can be about 0.1 toabout 0.9. The contacting can be carried out in the presence of a base,wherein the base can be triethylamine. The contacting can also becarried out in the presence of a solvent, wherein the solvent can beN,N-dimethylacetamide. The contacting can also be carried out at atemperature of about 50° C. to about 100° C. The contacting canpreferably occur for about 10 hours to about 24 hours. The polymer offormula (VI can also optionally be purified.

[0060] The present invention also provides a polymer of formula (XI):

[0061] wherein

[0062] m is about 0.1 to about 0.9;

[0063] p is about 0.9 to about 0.1;

[0064] n is about 50 to about 150;

[0065] each R² is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl;

[0066] each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl;

[0067] each R⁴ is independently (C₂-C₂)alkylene; and

[0068] each R⁶ is independently (C₂-C₂₀)alkylene or(C₂-C₈)alkyloxy(C₂-C₂₀)alkylene;

[0069] comprising one or more subunits of the formula (VIII):

[0070] wherein

[0071] each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; and

[0072] R⁴ is independently (C₂-C₂₀)alkylene;

[0073] R⁶ is independently (C₂-C₂₀)alkylene or(C₂-C₈)alkyloxy(C₂-C₂₀)alkylene; and

[0074] one or more subunits of the formula (IX):

[0075] wherein

[0076] the total number of subunits (VIII) and (IV) is about 50 to about150;

[0077] R² is independently hydrogen, (C₁-C₆)alkyl, or(C₆-C₁₀)aryl(C₁-C₆)alkyl.

[0078] Specifically, R² can independently be hydrogen or benzyl; each R³can independently be iso-butyl or benzyl; R⁴ can independently be(CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂)₁₂; and R⁶ can independently be (CH₂)₃or (CH₂)₂—O—(CH₂)₂.

[0079] The present invention also provides a polymer of formula (XI):

[0080] wherein

[0081] m is about 0.1 to about 0.9;

[0082] p is about 0.9 to about 0.1;

[0083] n is about 50 to about 150;

[0084] each R² is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl;

[0085] each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl;

[0086] each R⁴ is independently (C₂-C₂₀)alkylene; and

[0087] each R⁶ is independently (C₂-C₂₀)alkylene or(C₂-C₈)alkyloxy(C₂-C₂₀)alkylene.

[0088] Specifically, each R² can independently be hydrogen or benzyl;each R³ can independently be iso-butyl or benzyl; each R⁴ canindependently be (CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂)₁₂; each R⁶ canindependently be (CH₂)₃ or (CH₂)₂—O—(CH₂)₂; p/(p+m) can be about 0.9 toabout 0.1; and m/(p+m) can be about 0.1 to about 0.9.

[0089] The present invention also provides a polymer of formula (XI)formed from an amount of one or more compounds of formula (III):

[0090] wherein

[0091] each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁C₆)alkyl; and

[0092] R⁴ is independently (C₂-C₂₀)alkylene; or a suitable salt thereof;and an amount of one or more compounds of formula (IV):

[0093] wherein

[0094] R² is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; or asuitable salt thereof; and

[0095] an amount of one or more compounds of formula (X):

[0096] wherein

[0097] each R⁵ is independently (C₆-C₁₀)aryl optionally substituted withone or more nitro, cyano, halo, trifluoromethyl, or trifluoromethoxy;and

[0098] R⁶ is independently (C₂-C₂₀)alkylene or(C₂-C₈)alkyloxy(C₂-C₂₀)alkylene.

[0099] Specifically, R² can independently be hydrogen or benzyl; each R³can independently be iso-butyl or benzyl; R⁴ can independently be(CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂)₁₂; each R⁵ can be p-nitrophenyl; R⁶ canindependently be (CH₂)₃ or (CH₂)₂—O—(CH₂)₂; the compound of formula(III) can be the di-p-tolunesulfonic acid salt of a bis-(L-α-aminoacid)α,ω-alkylene diester; the compound of formula (IV) can be thedi-p-tolunesulfonic acid salt of L-lysine benzyl ester, the compound offormula (X) can be 1,3-bis (4-nitro-phenoxycarbonyloxy) propane; or2,2′-bis-4-nitrophenoxycarbonyloxy ethylether, p/(p+m) can be about 0.9to about 0.1; and m/(p+m) can be about 0.1 to about 0.9.

[0100] The present invention also provides a method for preparing apolymer of formula (XI):

[0101] wherein

[0102] m is about 0.1 to about 0.9;

[0103] p is about 0.9 to about 0.1;

[0104] n is about 50 to about 150;

[0105] each R² is independently hydrogen or (C₆-C₁₀)aryl(C₁-C₆)alkyl;

[0106] each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl;

[0107] each R⁴ is independently (C₂-C₂₀)alkylene;

[0108] each R⁵ is independently (C₆-C₁₀)aryl optionally substituted withone or more nitro, cyano, halo, trifluoromethyl, or trifluoromethoxy;and

[0109] each R⁶ is independently (C₂-C₂₀)alkylene or(C₂-C₈)alkyloxy(C₂-C₂₀)alkylene;

[0110] comprising contacting an amount of one or more compounds offormula (III):

[0111] or a suitable salt thereof; and

[0112] an amount of one or more compounds of formula (V):

[0113] or a suitable salt thereof; and

[0114] an amount of one or more compounds of formula (X):

[0115] under suitable conditions to provide the polymer of formula (XI).

[0116] Specifically, each R² can independently be hydrogen or benzyl;each R³ can independently be iso-butyl or benzyl; each R⁴ canindependently be (CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂)₁₂; each R⁵ can bep-nitrophenyl; each R⁶ can independently be (CH₂)₃ or (CH₂)₂—O—(CH₂)₂;the compound of formula (III) can be the di-p-tolunesulfonic acid saltof a bis-(L-α-amino acid)-α,ω-alkylene diester; the compound of formula(IV) can be the di-p-tolunesulfonic acid salt of L-lysine benzyl ester,the compound of formula (X) can be 1,3-bis (4-nitro-phenoxycarbonyloxy)propane, or 2,2′-bis-4-nitrophenoxycarbonyloxy ethylether; p/(p+m) canbe about 0.9 to about 0.1; and m/(p+m) can be about 0.1 to about 0.9.The contacting can be carried out in the presence of a base, wherein thebase can be triethylamine. The contacting can be carried out in thepresence of a solvent, wherein the solvent can be N,N-dimethylacetamide.The contacting can be carried out at a temperature of about 50° C. toabout 100° C. The contacting can occur for about 10 hours to about 24hours. In addition, the polymer of formula (XI) can optionally bepurified.

[0117] The biodegradation of the copolyester amides and copolyesterurethanes of the present invention allows the delivery of essentialα-amino acids to targeted sites (e.g., to facilitate wound repair ofinjured tissues). In addition, the polymers of the present invention canbe used for the attachment free iminoxyl radicals for suppressinginconsolable cell proliferation, and heparin or hirudin for increasinghemocompatibility. These modified polymers can be used to coat stents tosuppress restenosis. In addition, the polymers of the present inventioncan be used as polyacids for the application in gynecology asimpregnated contraceptive agents, e.g., for the controlled release offerrous gluconate and the like. Furthermore, the polymers of the presentinvention can be used as polyacids for the attachment of unsaturatedcompounds, e.g., allyl amine or allyl alcohol, to obtain photo-curableand cross-linkable biodegradable polymers. The present polymers can becross-linked with other polymers containing double bonds to createhybrid materials.

[0118] The biological and material properties of the polymers of thepresent invention can be varied over a wide range because the polymerscan be formed from starting materials having varying functional groups(e.g., dicarboxylic acids, diols, and α-amino acids). See, e.g.,Examples 1-22. In contrast to conventional poly(α-amino acids), theelastomeric functional copolyester amides and copolyester urethanes ofthe present invention can be obtained in high yields. See, Table III.For example, the compounds of the present invention can be prepared inyields up to about 97%. In addition, the reaction conditions employed toprepare the polymers of the present invention are relatively simple andthe reagents are relatively inexpensive.

[0119] The present invention also provides a polymer of formula (VI)that is linked to one or more drugs. The present invention also providesa polymer of formula (XI) that is linked to one or more drugs. A residueof the polymer can be linked directly to a residue of the drug. Theresidue of the polymer can be linked directly to the residue of the drugthrough an amide, ester, ether, amino, ketone, thioether, sulfinyl,sulfonyl, disulfide, or a direct linkage. The residue of the polymer canbe linked directly to the residue of the drug through one of thefollowing linkages: —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—,—C(═O)—, —S—, —S(O)—, —S(O)₂—, —S—S—, —N(R)—, or C—C; wherein each R isindependently H or (C₁-C₆)alkyl.

[0120] A residue of the polymer can be linked to a residue of the drug,through a linker. The linker can separate the residue of the polymer andthe residue of the drug by about 5 angstroms to about 200 angstroms,inclusive, in length. The residue of the polymer can be linked to thelinker and the linker can be linked to the residue of the drug,independently, through an amide, ester, ether, amino, ketone, thioether,sulfinyl, sulfonyl, disulfide, or a direct linkage. The residue of thepolymer can be linked to the linker and the linker can be linked to theresidue of the drug, independently, through one of the followinglinkages: —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—, —C(—O)—,—S—, —S(O)—, —S(O)₂—, —S—S—, —N(R)—, or C—C; wherein each R isindependently H or (C₁-C₆)alkyl. The linker can be a divalent radical ofthe formula W-A-Q wherein A is (C₁-C₂₄)alkyl, (C₂-C₂₄)alkenyl,(C₂-C₂₄)alkynyl, (C₃-C₈)cycloalkyl, or (C₆-C₁₀)aryl, wherein W and Q areeach independently —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—,—S—, —S(O)—, —S(O)₂—, —S—S—, —N(R)—, —C(═O)—, or a direct bond; whereineach R is independently H or (C₁-C₆)alkyl. The linker can be a1,ω-divalent radical formed from a peptide or an amino acid. The peptidecan comprise 2 to about 25 amino acids. The peptide can bepoly-L-lysine, poly-L-glutamic acid, poly-L-aspartic acid,poly-L-histidine, poly-L-omithine, poly-L-serine, poly-L-threonine,poly-L-tyrosine, poly-L-leucine, poly-L-lysine-L-phenylalanine,poly-L-arginine, or poly-L-lysine-L-tyrosine.

[0121] The one or more drugs can each independently be: apolynucleotide, polypeptide, oligonucleotide, gene therapy agent,nucleotide analog, nucleoside analog, polynucleic acid decoy,therapeutic antibody, abciximab, anti-inflammatory agent, bloodmodifier, anti-platelet agent, anti-coagulation agent, immunesuppressive agent, anti-neoplastic agent, anti-cancer agent, anti-cellproliferation agent, or nitric oxide releasing agent.

[0122] The present invention also provides a formulation comprising apolymer of formula (VI) and one or more drugs. The present inventionalso provides a formulation comprising a polymer of formula (XI) and oneor more drugs. The one or more drugs can each independently be: apolynucleotide, polypeptide, oligonucleotide, gene therapy agent,nucleotide analog, nucleoside analog, polynucleic acid decoy,therapeutic antibody, abciximab, anti-inflammatory agent, bloodmodifier, anti-platelet agent, anti-coagulation agent, immunesuppressive agent, anti-neoplastic agent, anti-cancer agent, anti-cellproliferation agent, or nitric oxide releasing agent.

[0123] The present invention also provides a method of using a polymerof the present invention for use as a medical device, a pharmaceutical,a carrier for covalent immobilization of a drug, or a bioactivesubstance.

DETAILED DESCRIPTION OF THE INVENTION

[0124] The following definitions are used, unless otherwise described:halo can be chloro, fluoro, bromo, or iodo. Alkyl, alkenyl, alkynyl,etc. denote both straight and branched groups; but reference to anindividual radical such as “propyl” embraces only the straight chainradical, a branched chain isomer such as “isopropyl” being specificallyreferred to.

[0125] It will be appreciated by those skilled in the art that compoundsof the invention having a chiral center may exist in and be isolated inoptically active and racemic forms. Some compounds may exhibitpolymorphism. It is to be understood that the present inventionencompasses any racemic, optically-active, polymorphic, orstereoisomeric form, or mixtures thereof, of a compound of theinvention, which possess the useful properties described herein, itbeing well known in the art how to prepare optically active forms (forexample, by resolution of the racemic form by recrystallizationtechniques, by synthesis from optically-active starting materials, bychiral synthesis, or by chromatographic separation using a chiralstationary phase).

[0126] The term “alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain preferably having from 1 to 40 carbon atoms,more preferably 1 to 10 carbon atoms, and even more preferably 1 to 6carbon atoms. This term is exemplified by groups such as methyl, ethyl,n-propyl, iso-propyl, -butyl, iso-butyl, n-hexyl, n-decyl, tetradecyl,and the like. As used herein, “alkyl” includes “substituted alkyl,”which refers to an alkyl group as defined above, having from 1 to 8substituents, preferably 1 to 5 substituents, and more preferably 1 to 3substituents, selected from the group consisting of alkoxy, cycloalkyl,acyl, amino, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxy,thiol, aryl, heteroaryl, heterocyclic, and nitro.

[0127] The term “alkaryl” refers to the groups -alkylene-aryl and-substituted alkylene-aryl where alkylene, substituted alkylene and arylare defined herein. Such alkaryl groups are exemplified by benzyl,phenethyl and the like.

[0128] The term “alkoxy” refers to the groups allyl-O—, alkenyl-O—,cycloalkyl-O—, cycloalkenyl-O—, and alkynyl-O—, where alkyl, alkenyl,cycloalkyl, cycloalkenyl, and alkynyl are as defined herein. Preferredalkoxy groups are alkyl-O— and include, by way of example, methoxy,ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy,n-pentoxy, n-hexoxy, 1,2-direthylbutoxy, and the like. As used herein,“alkoxy” includes “substituted alkoxy,” which refers to the groupssubstituted alkyl-O—, substituted alkenyl-O—, substituted cycloatkyl-O—,substituted cycloalkenyl-O—, and substituted alkynyl-O— wheresubstituted alkyl, substituted alkenyl, substituted cycloalkyl,substituted cycloalkenyl and substituted alkynyl are as defined herein.

[0129] The term “alkenyl” refers to a monoradical of a branched orunbranched unsaturated hydrocarbon group preferably having from 2 to 40carbon atoms, more preferably 2 to 10 carbon atoms and even morepreferably 2 to 6 carbon atoms and having at least 1 and preferably from1-6 sites of vinyl unsaturation. Preferred alkenyl groups includeethenyl (—CH═CH₂), in-propenyl (—CH₂CH═CH₂), iso-propenyl (—C(CH₃)═CH₂),and the like. As used herein, “alkenyl” includes “substituted alkenyl,”which refers to an alkenyl group as defined above having from 1 to 5substituents, and preferably 1 to 3 substituents, selected from thegroup consisting of alkoxy, substituted alkoxy, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino,acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxy,carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol,thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO- alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl.

[0130] The term “alkynyl” refers to a monoradical of an unsaturatedhydrocarbon preferably having from 2 to 40 carbon atoms, more preferably2 to 20 carbon atoms and even more preferably 2 to 6 carbon atoms andhaving at least 1 and preferably from 1-6 sites of acetylene (triplebond) unsaturation. Preferred alkynyl groups include ethynyl (—C—CH),propargyl (—CH₂C≡CH) and the like. As used herein, “alkynyl” includes“substituted alkynyl,” which refers to an alkynyl group as defined abovehaving from 1 to 5 substituents, and preferably 1 to 3 substituents,selected from the group consisting of alkoxy, substituted alkoxy,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,carboxy, carboxyalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryland —SO₂-heteroaryl.

[0131] The term “acyl” refers to the groups HC(O)—, alkyl-C(O)—,substituted alkyl-C(O)—, cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—,cycloalkenyl-C(O)—, substituted cycloalkenyl-C(O)—, aryl-C(O)—,heteroaryl-C(O)— and heterocyclic-C(O)— where alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, heteroaryl and heterocyclic are as defined herein.

[0132] The term “aryl” refers to an unsaturated aromatic carbocyclicgroup of from 6 to 20 carbon atoms having a single ring (e.g., phenyl)or multiple condensed (fused) rings, wherein at least one ring isaromatic (e.g., naphthyl, dihydrophenanthrenyl, fluorenyl, or anthryl).Preferred aryls include phenyl, naphthyl and the like.

[0133] Unless otherwise constrained by the definition for the arylsubstituent, such aryl groups can optionally be substituted with from 1to 5 substituents, preferably 1 to 3 substituents, selected from thegroup consisting of hydroxy, thiol, acyl, alkyl alkoxy, alkenyl,alkynyl, cycloalkyl aryl, azido, carboxy, cyano, halo, nitro,heteroaryl, heterocyclic, sulfonamide. Preferred aryl substituentsinclude alkyl, alkoxy, halo, cyano, nitro, and trihalomethyl.

[0134] The term “amino” refers to the group —NH₂.

[0135] The term “cycloalkyl” refers to cyclic alkyl groups of from 3 to20 carbon atoms having a single cyclic ring or multiple condensed rings.Such cycloalkyl groups include, by way of example, single ringstructures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, andthe like, or multiple ring structures such as adamantanyl, and the like.As used herein, “cycloalkyl” includes “substituted cycloalkyl,” whichrefers to cycloalkyl groups having from 1 to 5 substituents, andpreferably 1 to 3 substituents, selected from the group consisting ofalkoxy, cycloalkyl, acyl, amino, azido, cyano, halogen, hydroxyl, keto,carboxy, thiol, aryl, heteroaryl, heterocyclic, and nitro.

[0136] The term “halo” or “halogen” refers to fluoro, chloro, bromo andiodo.

[0137] “Haloalkyl” refers to allyl as defined herein substituted by 1-4halo groups as defined herein, which may be the same or different.Representative haloalkyl groups include, by way of example,trifluoromethyl, 3-fluorododecyl, 12,12,12-trifluorododecyl,2-bromooctyl, 3-bromo-6-chloroheptyl, and the like.

[0138] The term “heteroaryl” refers to an aromatic group of from 1 to 15carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen andsulfur within at least one ring (if there is more than one ring).

[0139] Unless otherwise constrained by the definition for the heteroarylsubstituent, such heteroaryl groups can be optionally substituted with 1to 5 substituents, preferably 1 to 3 substituents, selected from thegroup consisting of hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl,alkynyl, cycloalkyl, alkaryl, aryl, azido, carboxy, cyano, halo, nitro,heteroaryl, and heterocyclic. Preferred aryl substituents include alkyl,alkoxy, halo, cyano, nitro, and trihalomethyl. Such heteroaryl groupscan have a single ring (e.g., pyridyl or furyl) or multiple condensedrings (e.g., indolizinyl or benzothienyl). Preferred heteroaryls includepyridyl, pyrrolyl and furyl.

[0140] The term “heterocycle” or “heterocyclic” refers to a monoradicalsaturated or unsaturated group having a single ring or multiplecondensed rings, from 1 to 40 carbon atoms and from 1 to 10 heteroatoms, preferably 1 to 4 heteroatoms, selected from nitrogen, sulfur,phosphorus, and/or oxygen within the ring.

[0141] Unless otherwise constrained by the definition for theheterocyclic substituent, such heterocyclic groups can be optionallysubstituted with 1 to 5, and preferably 1 to 3 substituents, selectedfrom the group consisting of alkoxy, cycloalkyl, acyl, amino, azido,cyano, halogen, hydroxyl, keto, carboxy, thiol, aryl, and heterocyclic.Such heterocyclic groups can have a single ring or multiple condensedrings. Preferred heterocyclics include morpholino, piperidinyl, and thelike.

[0142] Examples of nitrogen heterocycles and heteroaryls include, butare not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine,quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine,quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline,phenanthridine, acridine, phenanthroline, isothiazole, phenazine,isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline,piperidine, piperazine, indoline, morpholino, piperidinyl,tetrahydrofuranyl, and the like as well as N-alkoxy-nitrogen containingheterocycles.

[0143] The term “saccharide group” refers to an oxidized, reduced orsubstituted saccharide monoradical covalently attached to theglycopeptide or other compound via any atom of the saccharide moiety,preferably via the aglycone carbon atom. The term includesamino-containing saccharide groups. Representative saccharides include,by way of illustration, hexoses such as D-glucose, D-mannose, D-xylose,D-galactose, vancosamine, 3-desmethyl-vancosamine, 3-epi-vancosamine,4-epi-vancosamine, acosamine, actinosamine, daunosamine,3-epi-daunosamine, ristosamine, D-glucamine, N-methyl-D-glucamine,D-glucuronic acid, N-acetyl-D-glucosamine, N-acetyl-D-galactosamine,sialyic acid, iduronic acid, L-fucose, and the like; pentoses such asD-ribose or D-arabinose; ketoses such as D-ribulose or D-fructose;disaccharides such as 2-O-(α-L-vancosaminyl)-p-D-glucopyranose,2-O-(3-desmethyl-α-L-vancosaminyl)-β-D-glucopyranose, sucrose, lactose,or maltose; derivatives such as acetals, amines, acylated, sulfated andphosphorylated sugars; oligosaccharides having from 2 to 10 saccharideunits. For the purposes of this definition, these saccharides arereferenced using conventional three letter nomenclature and thesaccharides can be either in their open or preferably in their pyranoseform. The “saccharide group” includes “amino-containing saccharidegroup” or “amino saccharide,” which refers to a saccharide group havingan amino substituent. Representative amino-containing saccharidesinclude L-vancosamine, 3-desmethyl-vancosamine, 3-epi-vancosamine,4-epi-vancosamine, acosamine, actinosamine, daunosamine,3-epi-daunosamine, ristosamine, N-methyl-D-glucamine and the like.

[0144] The term “stereoisomer” as it relates to a given compound is wellunderstood in the art, and refers another compound having the samemolecular formula, wherein the atoms making up the other compound differin the way they are oriented in space, but wherein the atoms in theother compound are like the atoms in the given compound with respect towhich atoms are joined to which other atoms (e.g. an enantiomer, adiastereomer, or a geometric isomer). See for example, Morrison andBoyde Organic Chemistiy, 1983, 4th ed., Allyn and Bacon, Inc., Boston,Mass., page 123.

[0145] The term “thiol” refers to the group —SH.

[0146] As to any of the above groups which contain one or moresubstituents, it is understood, of course, that such groups do notcontain any substitution or substitution patterns which are stericallyimpractical and/or synthetically non-feasible. In addition, thecompounds of this invention include all stereochemical isomers arisingfrom the substitution of these compounds.

[0147] “Cyclodextrin” refers to cyclic molecules containing six or moreα-D-glucopyranose units linked at the 1,4 positions by a linkages as inamylose. β-Cyclodextrin or cycloheptaamylose contains sevenα-D-glucopyranose units. As used herein, the term “cyclodextin” alsoincludes cyclodextrin derivatives such as hydroxypropyl and sulfobutylether cyclodextrins, and others. Such derivatives are described forexample, in U.S. Pat. Nos. 4,727,064 and 5,376,645. Additionally,hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin arecommercially available. One preferred cyclodextrin is hydroxypropylβ-cyclodextrin having a degree of substitution of from about 4.1-5.1 asmeasured by FUR. Such a cyclodextrin is available from Cerestar(Hammond, Ind., USA) under the name Cavitron™ 82003.

[0148] As used herein, an “amino acid” is a natural amino acid residue(e.g. Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Hyl, Hyp, Ile, Leu,Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val) in D or L form, as wellas unnatural amino acid (e.g. phosphoserine; phosphothreonine;phosphotyrosine; hydroxyproline; gamma-carboxyglutamate; hippuric acid;octahydroindole-2-carboxylic acid; statine;1,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid; penicillamine;ornithine; citruline; α-methyl-alanine; para-benzoylphenylalanine;phenylglycine; propargylglycine; sarcosine; and tert-butylglycine)residue having one or more open valences. The term also comprisesnatural and unnatural amino acids bearing amino protecting groups (e.g.acetyl, acyl, trifluoroacetyl, or benzyloxycarbonyl), as well as naturaland unnatural amino acids protected at carboxy with protecting groups(e.g. as a (C₁-C₆)alkyl, phenyl or benzyl ester or amide). Othersuitable amino and carboxy protecting groups are known to those skilledin the art (See for example, T. W. Greene, Protecting Groups In OrganicSynthesis; Wiley: New York, 1981; D. Voet, Biochemistry, Wiley: NewYork, 1990; L. Stryer, Biochemistry, (3rd Ed.), W. H. Freeman and Co.:New York, 1975; J. March, Advanced Organic Chemistry. Reactions,Mechanisms and Structure, (2nd Ed.), McGraw Hill: New York, 1977; F.Carey and R. Sundberg, Advanced Organic Chemistry. Part B: Reactions andSynthesis, (2nd Ed.), Plenum: New York, 1977; and references citedtherein). According to the invention, the amino or carboxy protectinggroup can also comprise a non-metallic radionuclide (e.g., Fluorine-18,Iodine-123, or Iodine-124).

[0149] The term “amino acid” includes alpha amino acids and beta aminoacids. The alpha amino acids include monocarboxylic monoamino acids,dicarboxylic monoamino acids, polyamino acids and heterocyclic aminoacids. Examples of monocarboxylic monoamino acids include glycine,alpha-phenylglycine, alpha-alanine, serine, valine, norvaline,beta-mercaptovaline, threonine, cysteine, leucine, isoleucine,norleucine, N-methylleucine, beta-hydroxy leucine, methionine,phenylalanine, N-methylphenylalanine, pipecolic acid, sarcosine,selenocysteine, tyrosine, 3,5-diiodotyrosine, triiodothyronine, andthyroxine. Examples of monoamino dicarboxylic acids and amides includeaspartic acid, beta-methyl aspartic acid, glutamic acid, asparagine,alpha-aminoadipic acid, 4-keto-pipecolic acid, lanthionine, andglutamine. Examples of polyamino acids include ornithine, lysine,6-N-methyllysine, 5-hydroxylysine, desmosine, arginine and cystine.Examples of heterocyclic amino acids include proline, 4-hydroxyprolineand histidine, and tryptophan. Examples of other alpha amino acids aregamma-carboxyglutamate and citrulline. The beta amino acids include, forexample, beta-alanine.

[0150] As used herein, a “peptide” is a sequence of 2 to 25 amino acids(e.g. as defined hereinabove) or peptidic residues having one or moreopen valences. The sequence may be linear or cyclic. For example, acyclic peptide can be prepared or may result from the formation ofdisulfide bridges between two cysteine residues in a sequence. A peptidecan be linked through the carboxy terminus, the amino terminus, orthrough any other convenient point of attachment, such as, for example,through the sulfur of a cysteine. Peptide derivatives can be prepared asdisclosed in U.S. Pat. Nos. 4,612,302; 4,853,371; and 4,684,620. Peptidesequences specifically recited herein are written with the aminoterminus on the left and the carboxy terminus on the right.

[0151] Specific and preferred values listed below for radicals,substituents, and ranges, are for illustration only; they do not excludeother defined values or other values within defined ranges for theradicals and substituents.

[0152] A specific value for R¹ is (CH₂)₄, (CH₂)₈, or (CH₂)₁₂.

[0153] A specific value for R² is hydrogen, benzyl, or phenethyl.Another specific value for R² is benzyl.

[0154] A specific value for R³ is iso-butyl or benzyl.

[0155] A specific value for R⁴ is (CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂)₁₂.

[0156] A specific value for R⁵ is p-nitrophenyl.

[0157] A specific value for R⁶ is (CH₂)₃ or (CH₂)₂—O—(CH₂)₂.

[0158] A specific value for m is about 0.25 to about 0.75.

[0159] A specific value for p is about 0.75 to about 0.25.

[0160] A specific value for n is about 75 to about 125.

[0161] A specific value for p/(p+m) is about 0.75 to about 0.25.

[0162] A specific value for m/(p+m) is about 0.25 to about 0.75.

[0163] A specific value for (p+m) is about 0.9 to about 1.1. Anotherspecific value for (p+m) is about 0.75 to about 1.25.

[0164] A specific group of compounds of formula (III) are thedi-p-tolunesulfonic acid salts of a bis-(L-α-amino acid)α,ω-alkylenediester:

[0165] wherein

[0166] each R³ is independently iso-butyl or benzyl; and

[0167] R⁴ is (CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂)₁₂.

[0168] A specific group of compounds of formula (V) are thedi-p-tolunesulfonic acid salts of L-lysine arylalkyl esters:

[0169] wherein

[0170] R² is benzyl or phenethyl. More specifically, R² can be benzyl.

[0171] A specific group of compounds of formula (V) are compounds of theformula:

[0172] wherein

[0173] R¹ is (CH₂)₄ (CH₂)₈, or (CH₂)₁₂; and

[0174] R⁵ is p-nitrophenyl.

[0175] For example, a specific group of compounds of formula (V) aredi-p-nitrophenyl adipate, di-p-nitrophenyl sebacinate, anddi-p-nitrophenyl dodecyldicarboxylate

[0176] A specific group of compounds of formula (X) are compounds of theformula:

[0177] wherein

[0178] R⁵ is p-nitrophenyl; and

[0179] R⁶ is (CH₂)₃ or (CH₂)₂—O—(CH₂)₂

[0180] For example, a specific group of compounds of formula (X) are1,3-bis (4-nitro-phenoxycarbonyloxy) propane and2,2′-bis-4-(nitrophenoxycarbonyloxy)ethylether.

[0181] In cases where compounds (e.g., starting materials) aresufficiently basic or acidic to form stable nontoxic acid or base salts,the compounds can exist as the acceptable salt. Examples of acceptablesalts are organic acid addition salts formed with acids which form anacceptable anion, for example, tosylate, methanesulfonate, acetate,citrate, malonate, tararate, succinate, benzoate, ascorbate,α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts mayalso exist, including hydrochloride, sulfate, nitrate, bicarbonate, andcarbonate salts.

[0182] Acceptable salts may be obtained by using standard proceduresthat are well known in the art, for example by reacting a sufficientlybasic compound such as an amine with a suitable acid affording anacceptable anion. Alkali metal (for example, sodium, potassium orlithium) or alkaline earth metal (for example calcium) salts ofcarboxylic acids can also be made.

[0183] Processes for preparing polymers of the present invention (e.g.,polymers of formula (VII) and polymers of formula (XI)) are provided asfurther embodiments of the invention and are illustrated by theprocedures herein below in which the meanings of the generic radicalsare as given above unless otherwise qualified.

[0184] A polymer of formula (Vet) can include one or more subunits offormula (I) and one or more subunits of formula (II); As such, a polymerof formula (VII) can be prepared from a compound of formula (III), froma compound of formula (IV), and from a compound of formula (V).Specifically, a polymer of formula (VII) can be prepared by contacting acompound of formula (III), a compound of formula (IV), and a compound offormula (V) under suitable conditions to provide a polymer of formula(VII).

[0185] The compounds of formula (III), (IV), and (V) can be contacted inthe presence of a solvent. Any suitable solvent can be employed. Whenthe compounds of formula (III), (IV), and (V) are contacted in thepresence of a solvent, the compounds of formula (III), (IV), and (V) arepreferably soluble in the solvent. One exemplary suitable solvent isN,N-dimethylacetamide.

[0186] The compounds of formula (III), (IV), and (V) can be contacted inthe presence of a base. Any suitable base can be employed. When thecompounds of formula (III), (IV), and (V) are contacted in the presenceof a base, the base will preferably adjust the initial pH of thereaction mixture (i.e., the solution including the compounds of formula(III), (IV), and (V)) above about 7. The base is useful to yield thefree amines of the compound of formula (III) and the compound of formula(IV). One exemplary suitable base is triethylamine.

[0187] The compounds of formula (III), (IV), and (V) can be contactedfor a period of time sufficient to provide the polymer of formula (VII).For example, the period of time can be from about 1 hour to about 48hours, inclusive. Preferably, the period of time can be from about 5hours to about 30 hours, inclusive. More preferably, the period of timecan be from about 10 hours to about 24 hours, inclusive.

[0188] The compounds of formula (III), (IV), and (V) can be contacted ata temperature sufficient to provide the polymer of formula (VII). Forexample, the temperature can be from the freezing point of the liquidreaction mixture (e.g., the solvent, base, and the compounds of formula(III), (IV), and (V)) up to about the reflux temperature of the reactionmixture. Preferably, the temperature can be from about 25° C. to about150° C. More preferably, the temperature can be from about 50° C. toabout 100° C.

[0189] A polymer of formula (XI) can include one or more subunits offormula (VIII) and one or more subunits of formula (IX). As such, apolymer of formula (XI) can be prepared from a compound of formula(III), from a compound of formula (IV), and from a compound of formula(X). Specifically, a polymer of formula (XI) can be prepared bycontacting a compound of formula (III), a compound of formula (IV), anda compound of formula (X) under suitable conditions to provide a polymerof formula (XI).

[0190] The compounds of formula (III), (IV), and (X) can be contacted inthe presence of a solvent. Any suitable solvent can be employed. Whenthe compounds of formula (III), (IV), and (X) are contacted in thepresence of a solvent, the compounds of formula (III), (IV), and (X) arepreferably soluble in the solvent. One exemplary suitable solvent isN,N-dimethylacetamide.

[0191] The compounds of formula (III), (IV), and (X) can be contacted inthe presence of a base. Any suitable base can be employed. When thecompounds of formula (III), (IV), and (X) are contacted in the presenceof a base, the base will preferably adjust the initial pH of thereaction mixture (i.e., the solution including the compounds of formula(III), (IV), and (X)) above about 7. The base is useful to yield thefree amines of the compound of formula (III) and the compound of formula(IV). One exemplary suitable base is triethylamine.

[0192] The compounds of formula (III) (IV), and (X) can be contacted fora period of time sufficient to provide the polymer of formula (VII). Forexample, the period of time can be from about 1 hour to about 48 hours,inclusive. Preferably, the period of time can be from about 5 hours toabout 30 hours, inclusive. More preferably, the period of time can befrom about 10 hours to about 24 hours, inclusive.

[0193] The compounds of formula (III), (IV), and (X) can be contacted ata temperature sufficient to provide the polymer of formula (VII). Forexample, the temperature can be from about the freezing point of theliquid reaction mixture (e.g., the solvent, base, and the compounds offormula (III) (IV), and (X)) up to about the reflux temperature of thereaction mixture. Preferably, the temperature can be from about 25° C.to about 150° C. More preferably, the temperature can be from about 50°C. to about

[0194] Polymer and Drug

[0195] A polymer of the present invention can include one or more drugs.In one embodiment, a polymer of the present invention can be physicallyintermixed with one or more drugs. In another embodiment, a polymer ofthe present invention can be linked to one or more drugs, eitherdirectly or through a linker. In another embodiment, a polymer of thepresent invention can be linked to one or more drugs, either directly orthrough a linker, and the resulting polymer can be physically intermixedwith one or more drugs.

[0196] As used herein, a “polymer of the present invention” includes acompound of formula (VII), a compound of formula (XI), or a combinationthereof.

[0197] Polymer/Drug Linkage

[0198] The present invention provides a polymer of the present invention(e.g., a compound of formula (VII) or a compound of formula (XI))directly linked to one or more drugs. In such an embodiment, theresidues of the polymer can be linked to the residues of the one or moredrugs. For example, one residue of the polymer can be directly linked toone residue of the drug. The polymer and the drug can each have one openvalence. Alternatively, more than one drug can be directly linked to thepolymer. In such an embodiment, the residue of each drug can be linkedto a corresponding residue of the polymer. As such, the number ofresidues of the one or more drugs can correspond to the number of openvalences on the residue of the polymer.

[0199] As used herein, a “residue of a polymer of the present invention”refers to a radical of a polymer of the present invention having one ormore open valences. Any synthetically feasible atom, atoms, orfunctional group of the polymer (e.g., on the polymer backbone orpendant group) of the present invention can be removed to provide theopen valence, provided bioactivity is substantially retained when theradical is attached to a residue of a drug. Additionally, anysynthetically feasible functional group (e.g., carboxyl) can be createdon the polymer (e.g., on the polymer backbone or pendant group) toprovide the open valence, provided bioactivity is substantially retainedwhen the radical is attached to a residue of a drug. Based on thelinkage that is desired, one skilled in the art can select suitablyfunctionalized starting materials that can be derived from the polymerof the present invention using procedures that are known in the art.

[0200] As used herein, a “residue of a compound of formula (VII)” refersto a radical of a compound of formula (VII) having one or more openvalences. Any synthetically feasible atom, atoms, or functional group ofthe compound of formula (VII) (e.g., on the polymer backbone or pendantgroup) can be removed to provide the open valence, provided bioactivityis substantially retained when the radical is attached to a residue of adrug. Additionally, any synthetically feasible functional group (e.g.,carboxyl) can be created on the compound of formula (II) (e.g., on thepolymer backbone or pendant group) to provide the open valence, providedbioactivity is substantially retained when the radical is attached to aresidue of a drug. Based on the linkage that is desired, one skilled inthe art can select suitably functionalized staring materials that can bederived from the compound of formula (VII) using procedures that areknown in the art.

[0201] As used herein, a “residue of a compound of formula (XI)” refersto a radical of a compound of formula (XI) having one or more openvalences. Any synthetically feasible atom, atoms, or functional group ofthe compound of formula (XI) (e.g., on the polymer backbone or pendantgroup) can be removed to provide the open valence, provided bioactivityis substantially retained when the radical is attached to a residue of adrug. Additionally, any synthetically feasible functional group (e.g.,carboxyl) can be created on the compound of formula (XI) (e.g., on thepolymer backbone or pendant group) to provide the open valence, providedbioactivity is substantially retained when the radical is attached to aresidue of a drug. Based on the linkage that is desired, one skilled inthe art can select suitably functionalized starting materials that canbe derived from the compound of formula (XI) using procedures that areknown in the art.

[0202] The residue of a drug can be linked to the residue of a compoundof formula (VII) or (XI) through an amide (e.g., —N(R)C(═O)— or—C(═O)N(R)—), ester (e.g., —OC(═O)— or —C(═O)O—), ether (e.g., —O—),amino (e.g., —N(R)—), ketone (e.g., —C(—O)—), thioether (e.g., —S—),sulfinyl (e.g., —S(O)—), sulfonyl (e.g., —S(O)₂—), disuffide (e.g.,—S—S—), or a direct (e.g., C—C bond) linkage, wherein each R isindependently H or (C₁-C₆)alkyl. Such a linkage can be formed fromsuitably functionalized starting materials using synthetic proceduresthat are known in the art. Based on the linkage that is desired, oneskilled in the art can select suitably functional starting materialsthat can be derived from a residue of a compound of formula (VII) or(XI) and from a given residue of a drug using procedures that are knownin the art. The residue of the drug can be directly linked to anysynthetically feasible position on the residue of a compound of formula(VII) or (XI). Additionally, the invention also provides compoundshaving more than one residue of a drug or drugs directly linked to acompound of formula (VII) or (XI).

[0203] One or more drugs can be linked directly to the polymer.Specifically, the residue of each of the drugs can each be directlylinked to the residue of the polymer. Any suitable number of drugs(i.e., residues thereof) can be directly linked to the polymer (i.e.,residue thereof). The number of drugs that can be directly linked to thepolymer can typically depend upon the molecular weight of the polymer.For example, for a compound of formula (VII), wherein n is about 50 toabout 150, up to about 450 drugs (i.e., residues thereof) can bedirectly linked to the polymer (i.e., residue thereof), up to about 300drugs (i.e., residues thereof) can be directly linked to the polymer(i.e., residue thereof), or up to about 150 drugs (i.e., residuesthereof) can be directly linked to the polymer (i.e., residue thereof).Likewise, for a compound of formula (XI), wherein n is about 50 to about150, up to about 450 drugs (i.e., residues thereof) can be directlylinked to the polymer (i.e., residue thereof), up to about 300 drugs(i.e., residues thereof) can be directly linked to the polymer (i.e.,residue thereof), or up to about 150 drugs (i.e., residues thereof) canbe directly linked to the polymer (i.e., residue thereof).

[0204] The residue of a polymer of the present invention, the residue ofa compound of formula (VII), and/or the residue of a compound of formula(XI) can be formed employing any suitable reagents and reactionconditions. Suitable reagents and reaction conditions are disclosed,e.g., in Advanced Organic Chemistry Part B: Reactions and Synthesis,Second Edition, Carey and Sundberg (1983); Advanced Organic Chemistry,Reactions, Mechanisms, and Structure, Second Edition, March (1977); andComprehensive Organic Transformations, Second Edition, Larock (1999).

[0205] In one embodiment of the present invention, a polymer (i.e.,residue thereof) of the present invention can be linked to the drug(i.e., residue thereof) via the carboxyl group (e.g., COOR²) of thepolymer. Specifically, a compound of formula (VII), wherein R² isindependently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; a compound offormula (XI), wherein R² is independently hydrogen, or(C₆-C₁₀)aryl(C₁-C₆)alkyl; or a combination thereof, can react with anamino functional group of the drug or a hydroxyl functional group of thedrug, to provide a Polymer/Drug having an amide linkage or aPolymer/Drug having a carboxylic ester linkage, respectively. In anotherembodiment, the carboxyl group of the polymer can be transformed into anacyl halide or an acyl anhydride.

[0206] Drug

[0207] As used herein, a “drug” refers to a therapeutic agent or adiagnostic agent and includes any substance, other than food, used inthe prevention, diagnosis, alleviation, treatment, or cure of a disease.Stedman's Medical Dictionary, 25^(th) Edition, Illustrated (1990) p.486. The substance can be taken by mouth; injected into a muscle, theskin, a blood vessel, or a cavity of the body; or topically applied.Mosby's Medical, Nursing & Allied Health Dictionary, Fifth Edition,(1998) p. 516. The drug can include any substance disclosed in at leastone of: The Merck Index, 12^(th) Edition (1996); Concise Dictionary ofBiomedicine and Molecular Biology, Pei-Show Juo, (1996); U.S.Pharmacopeia Dictionary, 2000 Edition; and Physician's Desk Reference,2001 Edition.

[0208] Specifically, the drug can include, but is not limited to, one ormore: polynucleotides, polypeptides, oligonucleotides, gene therapyagents, nucleotide analogs, nucleoside analogs, polynucleic acid decoys,therapeutic antibodies, abciximab, anti-inflammatory agents, bloodmodifiers, anti-platelet agents, anti-coagulation agents, immunesuppressive agents, anti-neoplastic agents, anti-cancer agents,anti-cell proliferation agents, and nitric oxide releasing agents.

[0209] The polynucleotide can include deoxyribonucleic acid (DNA),ribonucleic acid (RNA), double stranded DNA, double stranded RNA, duplexDNA/RNA, antisense polynucleotides, functional RNA or a combinationthereof. In one embodiment, the polynucleotide can be RNA. In anotherembodiment, the polynucleotide can be DNA In another embodiment, thepolynucleotide can be an antisense polynucleotide. In anotherembodiment, the polynucleotide can be a sense polynucleotide. In anotherembodiment, the polynucleotide can include at least one nucleotideanalog. In another embodiment, the polynucleotide can include aphosphodiester linked 3′-5′ and 5′-3′ polynucleotide backbone.Alternatively, the polynucleotide can include non-phosphodiesterlinkages, such as phosphotioate type, phosphoramidate andpeptide-nucleotide backbones. In another embodiment, moieties can belinked to the backbone sugars of the polynucleotide. Methods of creatingsuch linkages are well known to those of skill in the art.

[0210] The polynucleotide can be a single-stranded polynucleotide or adouble-stranded polynucleotide. The polynucleotide can have any suitablelength. Specifically, the polynucleotide can be about 2 to about 5,000nucleotides in length, inclusive; about 2 to about 1000 nucleotides inlength, inclusive; about 2 to about 100 nucleotides in length,inclusive; or about 2 to about 10 nucleotides in length, inclusive.

[0211] An antisense polynucleotide is typically a polynucleotide that iscomplimentary to an mRNA, which encodes a target protein. For example,the mRNA can encode a cancer promoting protein i.e., the product of anoncogene. The antisense polynucleotide is complimentary to the singlestranded mRNA and will form a duplex and thereby inhibit expression ofthe target gene, i.e., will inhibit expression of the oncogene. Theantisense polynucleotides of the invention can form a duplex with themRNA encoding a target protein and will disallow expression of thetarget protein.

[0212] A “functional RNA” refers to a ribozyme or other RNA that is nottranslated.

[0213] A “polynucleic acid decoy” is a polynucleic acid which inhibitsthe activity of a cellular factor upon binding of the cellular factor tothe polynucleic acid decoy. The polynucleic acid decoy contains thebinding site for the cellular factor. Examples of cellular factorsinclude, but are not limited to, transcription factors, polymerases andribosomes. An example of a polynucleic acid decoy for use as atranscription factor decoy will be a double stranded polynucleic acidcontaining the binding site for the transcription factor. Alternatively,the polynucleic acid decoy for a transcription factor can be a singlestranded nucleic acid that hybridizes to itself to form a snap-backduplex containing the binding site for the target transcription factor.An example of a transcription factor decoy is the E2F decoy. E2F playsrole in transcription of genes that are involved with cell-cycleregulation and that cause cells to proliferate. Controlling E2F allowsregulation of cellular proliferation. For example, after injury (e.g.,angioplasty, surgery, stenting) smooth muscle cells proliferate inresponse to the injury. Proliferation may cause restenosis of thetreated area (closure of an artery through cellular proliferation).Therefore, modulation of E2F activity allows control of cellproliferation and can be used to decrease proliferation and avoidclosure of an artery. Examples of other such polynucleic acid decoys andtarget proteins include, but are not limited to, promoter sequences forinhibiting polymerases and ribosome binding sequences for inhibitingribosomes. It is understood that the invention includes polynucleic aciddecoys constructed to inhibit any target cellular factor.

[0214] A “gene therapy agent” refers to an agent that causes expressionof a gene product in a target cell through introduction of a gene intothe target cell followed by expression. An example of such a genetherapy agent would be a genetic construct that causes expression of aprotein, such as insulin, when introduced into a cell. Alternatively, agene therapy agent can decrease expression of a gene in a target cell.An example of such a gene therapy agent would be the introduction of apolynucleic acid segment into a cell that would integrate into a targetgene and disrupt expression of the gene. Examples of such agents includeviruses and polynucleotides that are able to disrupt a gene throughhomologous recombination. Methods of introducing and disrupting geneswith cells are well known to those of skill in the art.

[0215] An oligonucleotide of the invention can have any suitable length.Specifically, the oligonucleotide can be about 2 to about 100nucleotides in length, inclusive; up to about 20 nucleotides in length,inclusive; or about 15 to about 30 nucleotides in length, inclusive. Theoligonucleotide can be single-stranded or double-stranded. In oneembodiment, the oligonucleotide can be single stranded. Theoligonucleotide can be DNA or RNA. In one embodiment, theoligonucleotide can be DNA In one embodiment, the oligonucleotide can besynthesized according to commonly known chemical methods. In anotherembodiment, the oligonucleotide can be obtained from a commercialsupplier. The oligonucleotide can include, but is not limited to, atleast one nucleotide analog, such as bromo derivatives, azidoderivatives, fluorescent derivatives or a combination thereof.Nucleotide analogs are well known to those of skill in the art. Theoligonucleotide can include a chain terminator. The oligonucleotide canalso be used, e.g., as a cross linking reagent or a fluorescent tag.Many common linkages can be employed to couple an oligonucleotide of theinvention to another moiety, e.g., phosphate, hydroxyl, etc.Additionally, a moiety may be linked to the oligonucleotide through anucleotide analog incorporated into the oligonucleotide. In anotherembodiment, the oligonucleotide can include a phosphodiester linked3′-5′ and 5′-3′ oligonucleotide backbone. Alternatively, theoligonucleotide can include non-phosphodiester linkages, such asphosphotioate type, phosphoramidate and peptide-nucleotide backbones. Inanother embodiment, moieties can be linked to the backbone sugars of theoligonucleotide. Methods of creating such linkages are well known tothose of skill in the art.

[0216] Nucleotide and nucleoside analogues are well known on the art.Examples of such nucleoside analogs include, but are not limited to,Cytovene® (Roche Laboratories), Epivir® (Glaxo Wellcome), Gemza®(Lilly), Hivid® (Roche Laboratories), Rebetron®) (Schering), Videx®(Bristol-Myers Squibb), Zerit® (Bristol-Myers Squibb), and Zovirax®(Glaxo Wellcome). See, Physician's Desk Reference, 2001 Edition.

[0217] Polypeptides of the invention can have any suitable length.Specifically, the polypeptides can be about 2 to about 5,000 amino acidsin length, inclusive; about 2 to about 2,000 amino acids in length,inclusive; about 2 to about 1,000 amino acids in length, inclusive; orabout 2 to about 100 amino acids in length, inclusive.

[0218] The polypeptides of the invention can also include “Peptidemimetics”. Peptide analogs are commonly used in the pharmaceuticalindustry as non-peptide drugs with properties analogous to those of thetemplate peptide. These types of non-peptide compound are termed“peptide mimetics” or “peptidomrimetics”. Fauchere, J. (1986) Adv. DrugRes., 15:29; Veber and Freidinger (1985) TINS p.392; and Evans et al.(1987) J. Med. Chem., 30: 1229; and are usually developed with the aidof computerized molecular modeling. Generally, peptidomimetics arestructurally similar to a paradigm polypeptide (i.e., a polypeptide thathas a biochemical property or pharmacological activity), but have one ormore peptide linkages optionally replaced by a linkage selected from thegroup consisting of: —CH₂NH—, —CH₂S—, CH₂—CH₂—, —CH═CH—(cis and trans),—COCH₂—CH(OH)CH₂—, and —CH₂SO—, by methods known in the art and furtherdescribed in the following references: Spatola, A. F. in “Chemistry andBiochemistry of Amino Acids, Peptides, and Proteins,” B. Weinstein,eds., Marcel Dekker, New York, p. 267 (1983); Spatola, A. F., Veea Data(arch 1983), Vol. 1, Issue 3, “Peptide Backbone Modifications” (generalreview); Morley, J. S., Trends. Pharm. Sci., (1980) pp. 463468 (generalreview); Hudson, D. et al., Int. J. Pept. Prot. Res., (1979) 14:177-185(—CH₂ NH—, CH₂CH₂—); Spatola, A. F. et al., Life Sci. (1986)38:1243-1249 (—CH₂—S—); Harm, M. M., J. Chem. Soc. Perkin Trans I (1982)307-314 (—CH═CH—, cis and trans); Almquist, R. G. et al., J. Med. Chem.,(1980) 23:1392-1398 (—COCH₂—); Jennings-White, C. et al., TetrahedronLett., (1982) 23:2533 (—COCH₂—) Szelke, M. et al., European Appln., EP45665 (1982) CA: 97:39405 (1982) (—CH(OH)CH₂—); Holladay, M. W. et al.,Tetrahedron Lett., (1983) 24:4401-4404 (—C(OH)CH₂—); and Hruby, V. J.,Life Sci., (1982) 31:189-199 (—CH₂—S—). Such peptide mimetics may havesignificant advantages over polypeptide embodiments, including, forexample: more economical production, greater chemical stability,enhanced pharmacological properties (half-life, absorption, potency,efficacy, etc.), altered specificity (e.g., a broad-spectrum ofbiological activities), reduced antigenicity, and others.

[0219] Additionally, substitution of one or more amino acids within apolypeptide with a D-amino acid of the same type (e.g., D-lysine inplace of L-lysine) may be used to generate more stable polypeptides andpolypeptides resistant to endogenous proteases.

[0220] In one embodiment, the polypeptide can be an antibody. Examplesof such antibodies include single-chain antibodies, chimeric antibodies,monoclonal antibodies, polyclonal antibodies, antibody fragments, Fabfragments, IgA, IgG, IgK, IgD, IgE and humanized antibodies. In oneembodiment, the antibody can bind to a cell adhesion molecule, such as acadherin, integrin or selectin. In another embodiment, the antibody canbind to an extracellular matrix molecule, such as collagen, elastin,fibronectin or laminin. In still another embodiment, the antibody canbind to a receptor, such as an adrenergic receptor, B-cell receptor,complement receptor, cholinergic receptor, estrogen receptor, insulinreceptor, low-density lipoprotein receptor, growth factor receptor orT-cell receptor. Antibodies of the invention can also bind to plateletaggregation factors (e.g., fibrinogen), cell proliferation factors(e.g., growth factors and cytokines), and blood clotting factors (e.g.,fibrinogen). In another embodiment, an antibody can be conjugated to anactive agent, such as a toxin. In another embodiment, the antibody canbe Abciximab (ReoProR)). Abciximab is an Fab fragment of a chimericantibody that binds to beta(3) integrins. Abciximab is specific forplatelet glycoprotein IIb/IIIa receptors, e.g., on blood cells. Humanaortic smooth muscle cells express alpha(v)beta(3) integrins on theirsurface. Treating beta(3) expressing smooth muscle cells may prohibitadhesion of other cells and decrease cellular migration orproliferation, thus reducing restinosis following percutaneous coronaryinterventions (CPI) e.g., stenosis, angioplasty, stenting. Abciximabalso inhibits aggregation of blood platelets.

[0221] In one embodiment, the peptide can be a glycopeptide.“Glycopeptide” refers to oligopeptide (e.g. heptapeptide) antibiotics,characterized by a multi-ring peptide core optionally substituted withsaccharide groups, such as vancomycin. Examples of glycopeptidesincluded in this definition may be found in “GlycopeptidesClassification, Occurrence, and Discovery”, by Raymond C. Rao and LouiseW. Crandall, (“Drugs and the Pharmaceutical Sciences” Volume 63, editedby Ramakrishnan Nagarajan, published by Marcal Dekker, Inc.). Additionalexamples of glycopeptides are disclosed in U.S. Pat. Nos. 4,639,433;4,643,987; 4,497,802; 4,698,327; 5,591,714; 5,840,684; and 5,843,889; inEP 0 802 199; EP 0 801 075; EP 0 667 353; WO 97/28812; WO 97/38702; WO98/52589; WO 98/52592; and in J. Amer. Chem. Soc., 1996, 118,13107-13108; J. Amer. Chem. Soc., 1997, 119, 12041-12047; and J. Amer.Chem. Soc., 1994, 116, 4573-4590. Representative glycopeptides includethose identified as A477, A35512, A40926, A41030, A42867, A47934,A80407, A82846, A83850 A84575, AB-65, Actaplanin, Actinoidin, Ardacin,Avoparcin, Azureomycin, Baihimycin, Chloroorientiein, Chloropolysporin,Decaplanin, -demethylvancomycm, Eremomycin, Galacardin, Helvecardin,Izupeptin, Kibdelin, LL-AM374, Mannopeptin, MM45289, MM47756, MM47761,MM49721, MM47766, MM55260, MM55266, MM55270, MM56597, MM56598, OA-7653,Orenticin, Parvodicin, Ristocetin, Ristomycin, Synmonicin, Teicoplanin,UK-68597, UK-69542, UK-72051, Vancomycin, and the like. The term“glycopeptide” or “glycopeptide antibiotic” as used herein is alsointended to include the general class of glycopeptides disclosed aboveon which the sugar moiety is absent, i.e. the aglycone series ofglycopeptides. For example, removal of the disaccharide moiety appendedto the phenol on vancomycin by mild hydrolysis gives vancomycinaglycone. Also included within the scope of the term “glycopeptideantibiotics” are synthetic derivatives of the general class ofglycopeptides disclosed above, included alkylated and acylatedderivatives. Additionally, within the scope of this term areglycopeptides that have been further appended with additional saccharideresidues, especially aminoglycosides, in a manner similar tovancosamine.

[0222] The term “lipidated glycopeptide” refers specifically to thoseglycopeptide antibiotics which have been synthetically modified tocontain a lipid substituent. As used herein, the term “lipidsubstituent” refers to any substituent contains 5 or more carbon atoms,preferably, 10 to 40 carbon atoms. The lipid substituent may optionallycontain from 1 to 6 heteroatoms selected from halo, oxygen, nitrogen,sulfur and phosphorous. Lipidated glycopeptide antibiotics arewell-known in the art. See, for example, in U.S. Pat. Nos. 5,840,684,5,843,889, 5,916,873, 5,919,756, 5,952,310, 5,977,062, 5,977,063, EP667, 353, WO 98/52589, WO 99/56760, WO 00/04044, WO 00/39156, thedisclosures of which are incorporated herein by reference in theirentirety.

[0223] Anti-inflammatory agents include, e.g., analgesics (e.g., NSAIDSand salicylates), antirheumatic agents, gastrointestinal agents, goutpreparations, hormones (glucocorticoids), nasal preparations, ophthalmicpreparations, otic preparations (e.g., antibiotic and steroidcombinations), respiratory agents, and skin & mucous membrane agents.See, Physician's Desk Reference, 2001 Edition. Specifically, theanti-inflammatory agent can include dexamethasone, which is chemicallydesignated as (11β,16α)-9-fluoro-11,17,21-trihydroxy-1,6-methylpregna-1,4-diene-3,20-dione.Alternatively, the anti-inflammatory agent can include sirolimus(rapamycin), which is a triene macrolide antibiotic isolated fromStreptomyces hygroscopicus.

[0224] Anti-platelet or anti-coagulation agents include, e.g., Coumadin®(DuPont), Fragmin® (Pharmacia & Upjohn), Heparin® (Wyeth-Ayerst),Lovenox®, Normiflo®, Orgaran® (Organon), Aggrastat® (Merck), Agrylin®D(Roberts), Ecotrin® (Smithkline Beecham), Flolan® (Glaxo Wellcome),Halfprin® (Kramer), Integrillin® (COR Therapeutics), Integrillin® (Key),Persantine® (Boehringer Ingelheim), Plavix® (Bristol-Myers Squibb),ReoPro® (Centecor), Ticlid® (Roche), Abbokinase® (Abbtt), Activase®(Genentech), Eminase® (Roberts), and Strepase® (Astra). See, Physician'sDesk Reference, 2001 Edition. Specifically, the anti-platelet oranti-coagulation agent can include trapidil (avantrin), cilostazol,heparin, hirudin, or ilprost.

[0225] Trapidil is chemically designated asN,N-dimethyl-5-methyl-[1,2,4]triazolo[1,-5-a]pyrimidin-7-amine.

[0226] Cilostazol is chemically designated as6-[(1-cyclohexyl-1H-tetrazol-5-yl)-butoxy]-3,4-dihydro-2(1H)-quinolinone.

[0227] Heparin is a glycosaminoglycan with anticoagulant activity; aheterogeneous mixture of vatiably sulfonated polysaccharide chainscomposed of repeating units of D-glucosamine and either L-iduronic orD-glucuronic acids.

[0228] Hirudin is an anticoagulant protein extracted from leeches, e.g.,Hirudo imiedicinalis.

[0229] Iloprost is chemically designated as5-[Hexahydro-5-hydroxy-4-(3-hydroxy-4-methyl-1-octen-6-ynyl)-2(1H)pentalenylidene]pentanoicacid.

[0230] The immune suppressive agent can include, e.g., Azathioprine®(Roxane), BayRho-D® (Bayer Biological), CellCept® (Roche Laboratories),Imuran® ((Glaxo Wellcome), MiCRhoGAM® (Ortho-Clinical Diagnostics),Neoran® (Novartis), Orthoclone OKT3® (Ortho Biotech), Prograf®(Fujisawa), PhoGAM® (Ortho-Clinical Diagnostics), Sandimune® (Novartis),Simulect® (Novartis), and Zenapax® (Roche Laboratories).

[0231] Specifically, the immune suppressive agent can include rapamycinor thalidomide.

[0232] Rapamycin is a triene macrolide isolated from Streptomyceshygroscopicus.

[0233] Thalidomide is chemically designated as2-(2,6-dioxo-3-piperidinyl)-1H-iso-indole-1,3(2H)-dione.

[0234] Anti-cancer or anti-cell proliferation agents include, e.g.,nucleotide and nucleoside analogs, such as 2-chloro-deoxyadenosine,adjunct antineoplastic agents, alkylating agents, nitrogen mustards,nitrosoureas, antibiotics, antimetabolites, hormonalagonists/antagonists, androgens, antiandrogens, antiestrogens, estrogen& nitrogen mustard combinations, gonadotropin releasing hotmone (GNRH)analogues, progestrins, immunomodulators, miscellaneous antineoplastics,photosensitizing agents, and skin & mucous membrane agents. See,Physician's Desk Reference, 2001 Edition.

[0235] Suitable adjunct antineoplastic agents include Anzemet® (HoeschstMarion Roussel), Aredia® (Novartis), Didronel® (MGI), Diflucan® Pfizer),Epogen® (Arngen), Ergamisol® (Janssen), Ethyol® (Alza), Kytril®(SmithKline Beecham), Leucovorin® (Immunex), Leucovorin® (GlaxoWellcome), Leucovorin® (Astra), Leukine®) (IMmunex), Marinol® (Roxane),Mesnex® (Bristol-Myers Squibb Oncology/Immunology, Neupogen (Amgen),Procrit® (Ortho Biotech), Salagen®D (MGI), Sandostatin®D (Novartis),Zinecard® (Pharmacia & Upjohn), Zofran® (Glaxo Wellcome) and Zyloprim®(Glaxo Wellcome).

[0236] Suitable miscellaneous alkylating agents include Myleran® (GlaxoWellcome), Paraplatin®D (Bristol-Myers Squibb Oncology/Immunology),Platinol® (Bristol-Myers Squibb Oncology/Immunology) and Thioplex®(Immunex).

[0237] Suitable nitrogen mustards include Alkeran® (Glaxo Wellcome),Cytoxan® (Bristol-Myers Squibb Oncology/Immunology), Ifex®(Bristol-Myers Squibb Oncology/Immunology), Leukeran® (Glaxo Wellcome)and Mustargen® (Merck).

[0238] Suitable nitrosoureas include BiCNU® (Bristol-Myers SquibbOncology/Immunology), CeeNU® (Bristol-Myers Squibb Oncology/Immunology),Gliadel® (Rhône-Poulenc Rover) and Zanosar® (Pharmacia & Upjohn).

[0239] Suitable antibiotics include Adriamycin PFS/RDF® (Pharmacia &Upjohn), Blenoxane® (Bristol-Myers Squibb Oncology/Immunology),Cerubidine® (Bedford), Cosmegen® Merck), DaunoXome® (NeXstar), Doxil®(Sequus), Doxorubicin Hydrochloride® (Astra), Idamycin® PFS (Pharmacia &Upjohn), Mithracin® (Bayer), Mitamnycin® (Bristol-Myers SquibbOncology/Immunology), Nipen®D (SuperGen), Novantrone® (Immunex) andRubex® (Bristol-Myers Squibb Oncology/Immunology).

[0240] Suitable antimetabolites include Cytostar-U® (Pharmacia &Upjohn), Fludara®b (Berlex), Sterile FUDR® (Roche Laboratories),Leustatin® (Ortho Biotech), Methotrexate® (Immunex), Parinethol® (GlaxoWellcome), Thioguanine® (Glaxo Wellcome) and Xeloda® (RocheLaboratories).

[0241] Suitable androgens include Nilandron® (Hoechst Marion Roussel)and Teslac® (Bristol-Myers Squibb Oncology/Immunology).

[0242] Suitable antiandrogens include Casodex® (Zeneca) and Eulexin®(Schering).

[0243] Suitable antiestrogens include Arimidex® (Zeneca), Fareston®g(Schering), Femara® (Novartis) and Nolvadex® (Zeneca).

[0244] Suitable estrogen & nitrogen mustard combinations include Emcyt®(Pharmacia & Upjohn).

[0245] Suitable estrogens include Estrace® (Bristol-Myers Squibb) andEstrab® (Solvay).

[0246] Suitable gonadotropin releasing hormone (GNRH) analogues includeLeupron Depot® (TAP) and Zoladex®) (Zeneca).

[0247] Suitable progestins include Depo-Provera® (Pharmacia & Upjohn)and Megace® (Bristol-Myers Squibb Oncology/Immunology).

[0248] Suitable immunomodulators include Erganisol® (Janssen) andProleukin® (Chiron Corporation).

[0249] Suitable miscellaneous antineoplastics include Camptosar®(Pharmacia & Upjohn), Celestone® (Schering), DTIC-Dome® (Bayer), Elspar®(Merck), Etopophos® (Bristol-Myers Squibb Oncology/Immunology),Etopoxide® (Astra), Gemzar® (Lilly), Hexalen® (U.S. Bioscience),Hycantin® (SmithKline Beecham), Hydrea® (Bristol-Myers SquibbOncology/Immunology), Hydroxyurea® (Roxane), Intron A® (Schering),Lysodren® (Bristol-Myers Squibb Oncology/Immunology), Navelbine® (GlaxoWellcome), Oncaspar® (Rhône-Poulenc Rover), Oncovin® (Lilly), Proleukin®(Chiron Corporation), Rituxan® (IDEC), Rituxan® (Genentech), Roferon-A®(Roche Laboratories), Taxol® (Bristol-Myers Squibb Oncology/Immunology),Taxotere® (Rhône-Poulenc Rover), TheraCys® (Pasteur Mérieux Connaught),Tice BCG® (Organon), Velban® (Lilly), VePesid® (Bristol-Myers SquibbOncology/Immunology), Vesanoid® (Roche Laboratories) and Vumon®(Bristol-Myers Squibb Oncology/Immunology).

[0250] Suitable photosensitizing agents include Photofrin® (Sanofi).

[0251] Specifically, the anti-cancer or anti-cell proliferation agentcan include Taxol® (paclitaxol), a niticoxide like compound, or NicOx(NCX-4016).

[0252] Taxol® (paclitaxol) is chemically designated as5β,20-Epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4,10-acetate2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine.

[0253] A niticoxide like compound includes any compound (e.g., polymer)to which is bound a nitric oxide releasing functional group. Suitableniticoxide like compounds are disclosed, e.g., in U.S. Pat. No.5,650,447 and S-nitrosothiol derivative (adduct) of bovine or humanserum albumin. See, e.g., Inhibition of neointimal proliferation inrabbits after vascular injury by a single treatment with a proteinadduct of nitric oxide; David marks et al J. Clin.Invest.(1995);96:2630-2638.

[0254] NCX-4016 is chemically designated as 2-acetoxy-benzoate2-(nitroxymethyl)-phenyl ester, and is an antithrombitic agent.

[0255] It is appreciated that those skilled in the art understand thatthe drug useful in the present invention is the biologically activesubstance present in any of the drugs or agents disclosed above. Forexample, Taxol® (paclitaxol) is typically available as an injectable,slightly yellow, viscous solution. The drug, however, is a crystallinepowder with the chemical name5β,20-Epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4,10-diacetate2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine.Physician's Desk Reference (PDR). Medical Economics Company (Montvale,N.J.), (53rd Ed.), pp. 1059-1067.

[0256] As used herein, a “residue of a drug” is a radical of a drughaving one or more open valences. Any synthetically feasible atom oratoms of the drug can be removed to provide the open valence, providedbioactivity is substantially retained when the radical is attached to aresidue of compound of formula (VII) or (XI). Based on the linkage thatis desired, one skilled in the art can select suitably functionalizedstarting materials that can be derived from a drug using procedures thatare known in the art.

[0257] The residue of a drug can be formed employing any suitablereagents and reaction conditions. Suitable reagents and reactionconditions are disclosed, e.g., in Advanced Organic Chemistry, Part B:Reactions and Synthesis, Second Edition, Carey and Sundberg (1983);Advanced Organic Chemistry, Reactions Mechanisms, and Structure, SecondEdition, March (1977); and Comprehensive Organic Transformations, SecondEdition, Larock (1999).

[0258] The polymer/drug linkage can degrade to provide a suitable andeffective amount of drug. Any suitable and effective amount of drug canbe released and will typically depend, e.g., on the specific polymer,drug, and polymer/drug linkage chosen. Typically, up to about 100% ofthe drug can be released from the polymer/drug. Specifically, up toabout 90%, up to 75%, up to 50%, or up to 25% of the drug can bereleased from the polymer/drug. Factors that typically affect the amountof the drug that is released from the polymer/drug include, e.g., thenature and amount of polymer, the nature and amount of drug, the natureof the polymer/drug linkage, and the nature and amount of additionalsubstances present in the formulation.

[0259] The polymer/drug linkage can degrade over a period of time toprovide the suitable and effective amount of drug. Any suitable andeffective period of time can be chosen. Typically, the suitable andeffective amount of drug can be released in about twenty-four hours, inabout seven days, in about thirty days, in about ninety days, or inabout one hundred and twenty days. Factors that typically affect thelength of time in which the drug is released from the polymer/druginclude, e.g., the nature and amount of polymer, the nature and amountof drug, the nature of the polymer/drug linkage, and the nature andamount of additional substances present in the formulation.

[0260] Polymer/Linker/Drug Linkage

[0261] In addition to being directly linked to the residue of a compoundof formula (VII) or (XI), the residue of a drug can also be linked tothe residue of a compound of formula (VII) or (XI) by a suitable linker.The structure of the linker is not crucial, provided the resultingcompound of the invention has an effective therapeutic index as a drug.

[0262] Suitable linkers include linkers that separate the residue of acompound of formula (VII) or (XI) and the residue of a drug by about 5angstroms to about 200 angstroms, inclusive, in length. Other suitablelinkers include linkers that separate the residue of a compound offormula (VII) or (I) and the residue of a drug by about 5 angstroms toabout 100 angstroms, inclusive, in length, as well as linkers thatseparate the residue of a compound of formula (VII) or (XI) and theresidue of a drug by about 5 angstroms to about 50 angstroms, or byabout 5 angstroms to about 25 angstroms, inclusive, in length.

[0263] The linker can be linked to any synthetically feasible positionon the residue of a compound of formula (VII) or (XI). Based on thelinkage that is desired, one skilled in the art can select suitablyfunctionalized starting materials that can be derived from a compound offormula (VII) or (XI) and a drug using procedures that are known in theart.

[0264] The linker can conveniently be linked to the residue of acompound of formula (VII) or (XI) or to the residue of a drug through anamide (e.g., —N(R)C(═O)— or —C(═O)N(R)—), ester (e.g., —OC(═O)— or—C(═O)O—), ether (e.g., —O—), ketone (e.g., —C(═O)—) thioether (e.g.,—S—), sulfinyl (e.g., —S(O)—), sulfonyl (e.g., —S(O)₂—), disulfide(e.g., —S—S—), amino (e.g., —N(R)—) or a direct (e.g., C—C) linkage,wherein each R is independently H or (C₁-C₆)alkyl. The linkage can beformed from suitably functionalized starting materials using syntheticprocedures that are known in the art. Based on the linkage that isdesired, one skilled in the art can select suitably functional startingmaterials that can be derived from a residue of a compound of formula(VII) or (I), a residue of a drug, and from a given linker usingprocedures that are known in the art.

[0265] Specifically, the linker can be a divalent radical of the formulaW-A-Q wherein A is (C₁-C₂₄)alkyl, (C₂-C₂₄)alkenyl, (C₂-C₂₄)alkynyl,(C₃-C₈)cycloalkyl, or (C₆-C₁₀)aryl wherein W and Q are eachindependently —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—, —S—,—S(O)—, —S(O)₂—, —S—S—, —N(R)—, C(═O)—, or a direct bond (i.e., W and/orQ is absent); wherein each R is independently H or (C₁-C₆)alkyl.

[0266] Specifically, the linker can be a divalent radical of the formulaW—(CH₂)-Q wherein, n is between about 1 and about 20, between about 1and about 15, between about 2 and about 10, between about 2 and about 6,or between about 4 and about 6; wherein W and Q are each independently—N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—, —S—, —S(O)—, —S(O)₂—,—S—S—, —C(═O)—, —N(R)—, or a direct bond (i.e., W and/or Q is absent);wherein each R is independently H or (C₁-C₆)alkyl.

[0267] Specifically, W and Q can each independently be —N(R)C(═O)—,—C(═O)N(R)—, —OC(═O)—, —N(R)—, —C(═O)O—, —O—, or a direct bond (i.e., Wand/or Q is absent).

[0268] Specifically, the linker can be a divalent radical formed from asaccharide.

[0269] Specifically, the linker can be a divalent radical formed from acyclodextrin.

[0270] Specifically, the linker can be a divalent radical, i.e.,1,ωdivalent radicals formed from a peptide or an amino acid. The peptidecan comprise 2 to about 25 amino acids, 2 to about 15 amino acids, or 2to about 12 amino acids.

[0271] Specifically, the peptide can be poly-L-lysine (i.e.,[—NHCH[(CH₂)₄NH₂]CO—]_(m)-Q, wherein Q is H, (C₁-C₁₄)alkyl, or asuitable carboxy protecting group; and wherein m is about 2 to about 25.Specifically, the poly-L-lysine can contain about 5 to about 15 residues(i.e., m is between about 5 and about 15). More specifically, thepoly-L-lysine can contain about 8 to about 11 residues (i.e., m isbetween about 8 and about 11).

[0272] Specifically, the peptide can be poly-L-glutamic acid,poly-L-aspartic acid, poly-L-histidine, poly-L-ornithine, poly-L-serine,poly-L-threonine, poly-L-tyrosine, poly-L-leucine,poly-L-lysine-L-phenylalanine, poly-L-arginine, orpoly-L-lysine-L-tyrosine.

[0273] Specifically, the linker can be prepared from 1,6-diaminohexaneH₂N(CH₂)₆NH₂, 1,5-diaminopentane H₂N(CH₂)NH₂, 1,4-diaminobutaneH₂N(CH₂)₄NH₂, or 1,3-diaminopropane H₂N(CH₂)₃NH₂.

[0274] One or more drugs can be linked to the polymer through a linker.Specifically, the residue of each of the drugs can each be linked to theresidue of the polymer through a linker. Any suitable number of drugs(i.e., residues thereof) can be linked to the polymer (i.e., residuethereof) through a linker. The number of drugs that can be linked to thepolymer, through a linker, can typically depend upon the molecularweight of the polymer. For example, for a compound of formula (VII),wherein n is about 50 to about 150, up to about 450 drugs (i.e.,residues thereof) can be linked to the polymer (i.e., residue thereof)through a linker, up to about 300 drugs (i.e., residues thereof) can belinked to the polymer (i.e., residue thereof) through a linker, or up toabout 150 drugs (i.e., residues thereof) can be linked to the polymer(i.e., residue thereof) through a linker. Likewise, for a compound offormula (XI), wherein n is about 50 to about 150, up to about 450 drugs(i.e., residues thereof) can be linked to the polymer (i.e., residuethereof) through a linker, up to about 300 drugs (i.e., residuesthereof) can be linked to the polymer (i.e., residue thereof) through alinker, or up to about 150 drugs (i.e., residues thereof) can be linkedto the polymer (i.e., residue thereof) through a linker.

[0275] In one embodiment of the present invention, a polymer (i.e.,residue thereof) of the present invention can be linked to the linkervia the carboxyl group (e.g., COOR²) of the polymer. Specifically, acompound of formula (VII), wherein R² is independently hydrogen, or(C₆-C₁₀)aryl(C₁-C₆)alkyl; a compound of formula (XI), wherein R² isindependently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; or a combinationthereof, can react with an amino functional group of the linker or ahydroxyl functional group of the linker, to provide a Polymer/Linkerhaving an amide linkage or a Polymer/Linker having a carboxyl esterlinkage, respectively. In another embodiment, the carboxyl group can betransformed into an acyl halide or an acyl anhydride.

[0276] In one embodiment of the present invention, a drug (i.e., residuethereof) can be linked to the linker via a carboxyl group (e.g., COOR,wherein R is hydrogen, (C₆-C₁₀)aryl(C₁-C₆)alkyl or (C₁-C₆)alkyl) of thelinker. Specifically, an amino functional group of the drug or ahydroxyl functional group of the drug can react with the carboxyl groupof the linker, to provide a Linker/Drug having an amide linkage or aLinker/Drug having a carboxylic ester linkage, respectively. In anotherembodiment, the carboxyl group of the linker can be transformed into anacyl halide or an acyl anhydride.

[0277] The polymer/linker/drug linkage can degrade to provide a suitableand effective amount of drug. Any suitable and effective amount of drugcan be released and will typically depend, e.g., on the specificpolymer, drug, linker, and polymer/linker/drug linkage chosen.Typically, up to about 100% of the drug can be released from thepolymer/linker/drug. Specifically, up to about 90%, up to 75%, up to50%, or up to 25% of the drug can be released from thepolymer/linker/drug. Factors that typically affect the amount of thedrug that is released from the polymer/linker/drug include, e.g., thenature and amount of polymer, the nature and amount of drug, the natureand amount of linker, the nature of the polymer/linker/drug linkage, andthe nature and amount of additional substances present in theformulation.

[0278] The polymer/linker/drug linkage can degrade over a period of timeto provide the suitable and effective amount of drug. Any suitable andeffective period of time can be chosen. Typically, the suitable andeffective amount of drug can be released in about twenty-four hours, inabout seven days, in about thirty days, in about ninety days, or inabout one hundred and twenty days. Factors that typically affect thelength of time in which the drug is released from thepolymer/linker/drug include, e.g., the nature and amount of polymer, thenature and amount of drug, the nature of the linker, the nature of thepolymer/linker/drug linkage, and the nature and amount of additionalsubstances present in the formulation.

[0279] Polymer Intermixed with Drug

[0280] In addition to being linked to one or more drugs, either directlyor through a linker, a polymer of the present invention can bephysically intermixed with one or more drugs to provide a formulation.

[0281] As used herein, “intermixed” refers to a polymer of the presentinvention physically mixed with a drug or a polymer of the presentinvention physically in contact with a drug.

[0282] As used herein, a “formulation” refers to a polymer of thepresent invention intermixed with one or more drugs. The formulationincludes a polymer of the present invention having one or more drugspresent on the surface of the polymer, partially embedded in thepolymer, or completely embedded in the polymer. Additionally, theformulation includes a polymer of the present invention and a drugforming a homogeneous composition (i.e., a homogeneous formulation).

[0283] Any suitable amount of polymer and drug can be employed toprovide the formulation. The polymer can be present in about 0.1 wt. %to about 99.9 wt. % of the formulation. Typically, the polymer can bepresent above about 25 wt. % of the formulation; above about 50 wt. % ofthe formulation; above about 75 wt. % of the formulation; or above about90 wt. % of the formulation. Likewise, the drug can be present in about0.1 wt. % to about 99.9 wt. % of the formulation. Typically, the drugcan be present above about 5 wt. % of the formulation; above about 10wt. % of the formulation; above about 15 wt. % of the formulation; orabove about 20 wt. % of the formulation.

[0284] The polymer/drug, polymer/linker/drug, formulation, orcombination thereof can be applied, as a polymeric film, onto thesurface of a medical device (e.g., stent). The surface of the medicaldevice can be coated with the polymeric film. The polymeric film canhave any suitable thickness on the medical device. For example, thethickness of the polymeric film on the medical device can be about 1 toabout 50 microns thick or about 5 to about 20 microns thick. Thepolymeric film can effectively serve as a drug eluting polymericcoating. This drug eluting polymeric coating can be created by anysuitable coating process, e.g., dip coating, vacuum depositing, or spraycoating the polymeric film, on the medical device. Additionally, thedrug eluting polymer coating system can be applied onto the surface of astent, a vascular delivery catheter, a delivery balloon, a separatestent cover sheet configuration, or a stent drug delivery sleeves typeof local drug delivery systems.

[0285] The drug eluting polymer coated stents can be used in conjunctionwith, e.g., hydrogel-based drug delivery systems.

[0286] In addition the above described polymer coated stent, variousdrugs mixed with hydrogels (see, U.S. Pat. No. 5,610,241) with differentelution rate can be applied on the top of the polymer coated stentsurface as a sandwich type of configuration to deliver anti restenoticagents to the blood vessels and prevent or reduce in-stent restenosis.

[0287] Any suitable size of polymer and drug can be employed to providethe formulation. For example, the polymer can have a size of less thanabout 1×10⁻⁴ meters, less than about 1×10⁻⁵ meters, less than about1×10⁻⁶ meters, less than about 1×10⁻⁷ meters, less than about 1×10⁻⁸meters, or less than about 1×10⁻⁹ meters.

[0288] The formulation can degrade to provide a suitable and effectiveamount of drug. Any suitable and effective amount of drug can bereleased and will typically depend, e.g., on the specific formulationchosen. Typically, up to about 100% of the drug can be released from theformulation. Specifically, up to about 90%, up to 75%, up to 50%, or upto 25% of the drug can be released from the formulation. Factors thattypically affect the amount of the drug that is released from theformulation include, e.g., the nature and amount of polymer, the natureand amount of drug, and the nature and amount of additional substancespresent in the formulation.

[0289] The formulation can degrade over a period of time to provide thesuitable and effective amount of drug. Any suitable and effective periodof time can be chosen. Typically, the suitable and effective amount ofdrug can be released in about twenty-four hours, in about seven days, inabout thirty days, in about ninety days, or in about one hundred andtwenty days. Factors that typically affect the length of time in whichthe drug is released from the formulation include, e.g., the nature andamount of polymer, the nature and amount of drug, and the nature andamount of additional substances present in the formulation.

[0290] The present invention provides for a formulation that includes apolymer of the present invention physically intermixed with one or moredrugs. The polymer that is present in the formulation can also belinked, either directly or through a linker, to one or more (e.g., 1, 2,3, or 4) drugs. As such, a polymer of the present invention can beintermixed with one or more (e.g., 1, 2, 3, or 4) drugs and can belinked, either directly or through a linker, to one or more (e.g., 1, 2,3, or 4) drugs.

[0291] A polymer of the present invention can include one or more drugs.In one embodiment, a polymer of the present invention can be physicallyintermixed with one or more drugs. In another embodiment, a polymer ofthe present invention can be linked to one or more drugs, eitherdirectly or through a linker. In another embodiment, a polymer of thepresent invention can be linked to one or more drugs, either directly orthrough a linker, and the resulting polymer can be physically intermixedwith one or more drugs.

[0292] A polymer of the present invention, whether or not present in aformulation as described herein, whether or not linked to a drug asdescribed herein, and whether or not intermixed with a drug as describedherein, can be used in medical therapy or medical diagnosis. Forexample, the polymer can be used in the manufacture of a medical device.Suitable medical devices include, e.g., artificial joints, artificialbones, cardiovascular medical devices, stents, shunts, medical devicesuseful in angioplastic therapy, artificial heart valves, artificialby-passes, sutures, artificial arteries, a vascular delivery catheters,a delivery balloons, separate stent cover sheet configurations, andstent drug delivery sleeve types of local drug delivery systems.

[0293] All publications, patents, and patent documents are incorporatedby reference herein, as though individually incorporated by reference.The invention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

[0294] The present invention will now be illustrated by the followingnon-limiting examples.

EXAMPLES

[0295] Preparation of copoly(ester amide)s (coPEAs) and copoly(esterurethane)s (coPEURs) (general procedure)

[0296] Dry triethylamine (Net) (30.8 mL, 0.22 mole) was added to amixture of predetermined quantities of the di-p-toluenesulfonic acidsalt of bis-(L-α-amino acid)α,ω-alkylene diester (III) and thedi-p-toluenesulfonic acid salt of L-lysine benzyl ester (IV) (totalamount of (III)+(IV) 0.1 mole), and active diester (V) or activebis-carbonate (IV) (0.1 mole) in dry N,N-dimethylacetamide (DMA) (52.5mL) (total volume of DMA and NEt₃ is 83.3 mL, concentration 1.2 mol/L by(III)+(IV) or by (V)) at room temperature. Afterwards, the temperatureof the reaction mixture was increased to about 80° C. and stirred forabout 16 hours. The viscous reaction solution was cooled to roomtemperature, diluted with ethanol (150 mL), and poured into cool water.The separated polymer was thoroughly washed with water, dried at about30° C. under reduced pressure (for final purification of coPEAs andcoPEURs see below). Reduced viscosity data (η_(red)) of the polymerswere obtained in m-cresol at a concentration of 0.5 g/dL and t=25° C.

[0297] Preparation of CoPEAs:

Example 1

[0298] Preparation ofco-poly-{[N,N′-adipoyl-bis-(L-leucine)-1,6-hexylenediester]}_(0.75)-{[N,N′-adipoyl-L-lysine benzyl ester]_(0.25)} (1)(compound of formula (VII) wherein m=0.75, p=0.25, n=75, R₁=(CH₂)₄,R₂=Bz, R₃=iso-propyl and R₄=(CH₂)₆).

[0299] Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixtureof the di-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylenediester (III, R⁴ (CH₂)₆) (50.168 g, 0.075 mole); thedi-p-toluenesulfonic acid salt of L-lysine benzyl ester (IV) (totalamount of (III)+(IV)=0.1 mole) (14.518 g, 0.025 mole); anddi-p-nitrophenyl adipate (V, R¹=(CH₂)₄) (38.833 g, 0.1 mole) in dryN,N-dimethylacetamide (52.5 mL) (total volume of DMA and NEt₃ is 83.3mL, concentration 1.2 mol/L by (III)+(IV) or by (V)) at roomtemperature. Afterwards, the temperature of the reaction mixture wasincreased to about 80° C. and stirred for about 16 hours. The viscousreaction solution was cooled to room temperature, diluted with ethanol(150 mL), and poured into water. The separated polymer was thoroughlywashed with water, dried at about 30° C. under reduced pressure. Afterfinal purification up to negative test on p-nitrophenol andp-toluenesulfonic acid (see below), yield is 90%, η_(red)=1.30 dL/g.Mw=32,100, Mn=27,000, Mw/Mn=1.19 (GPC in THF).

Example 2

[0300] Preparation ofco-poly-{[N,N′-sebacoyl-bis-(L-leucine)-1,6-hexylenediester]}_(0.75)-{[N,N′-sebacoyl-L-lysine benzyl ester]_(0.25)} (2)(compound of formula (VII) wherein m=0.75, p=0.25, n=65, R₁=(CH₂)₈,R₂=Bz, R₃=iso-propyl, and R₄=(CH₂)₆).

[0301] Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixtureof di-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylenediester (III, R⁴=(CH₂)₆) (50.168 g (0.075 mole); thedi-p-toluenesulfonic acid salt of L-lysine benzyl ester (IV) (14.518 g,0.025 mole) (total amount of (III)+(IV)=0.1 mole), and di-p-nitrophenylsebacinate (V, R¹=(CH₂)₈) (44.444 g, 0.1 mole) in dryN,N-dimethylacetamide (DMA) (52.5 mL) (total volume of DMA and NEt₃ is83.3 mL, concentration 1.2 mol/L by (E)+(IV) or by (V)) at roomtemperature. Afterwards, the temperature of the reaction mixture wasincreased to about 80° C. and stirred for about 16 hours. The viscousreaction solution was cooled to room temperature, diluted with ethanol(150 mL), and poured into water. The separated polymer was thoroughlywashed with water, dried at about 30° C. under reduced pressure. Afterfinal purification up to negative test on p-nitrophenol andp-toluenesulfonic acid (see below), yield is 91%, η_(red)=1.40 dL/g.Mw=31.300, Mn=21.000, Mw/Mn=1.49 (GPC in THF). Biodegradation (weightloss in %) at 37° C. after 120 h in phosphate buffer (pH 7.4): ˜0%weight loss in pure buffer, 1-2% in the buffer with α-chymotrypsin (4mg/10 mL of buffer), 1-2% in the buffer with lipase (4 mg/10 mL ofbuffer).

Example 3

[0302] Preparation of co-poly-{[N,N′-adipoyl-bis-(L-leucine)1,6-hexylenediester]}_(0.50)-[N,N′-adipoyl-bis-(L-phenylalanine)-1,6-hexylenediester]_(0.25)-{[N,N′-adipoyl-L-lysine benzyl ester]_(0.25)} (3)(compound of formula (VII) wherein m=0.50, p=0.50, R₁=(CH₂)₄, R₂=Bz,R₃=iso-propyl and Bz, and R₄=(CH₂)₆ and Bz).

[0303] Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixtureof the di-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylenediester (III, R⁴ (CH₂)₆) (34.446 g, 0.050 mole), thedi-p-toluenesulfonic acid salt of bis-(L-phenylalanine)1,6-hexylenediester (III, R⁴=CH₂Ph) (18.924 g, 0.025 mole), the di-p-toluenesulfonicacid salt of L-lysine benzyl ester (IV) (14.5180 g, 0.025 mole) (totalamount of (III)+(IV)=0.1 mole), and di-p-nitrophenyl adipate (V,R¹=(CH₂)₄) (38.833, 0.1 mole) in dry N,N-dimethylacetamide (DMA) (52.5mL of) (total volume of DMA and NEt₃ is 83.3 mL, concentration 1.2 mol/Lby (III)+(IV) or by (V)) at room temperature. Afterwards, thetemperature of the reaction mixture was increased to about 80° C. andstirred for about 16 hours. The viscous reaction solution was cooled toroom temperature, diluted with ethanol (150 mL), and poured into water.The separated polymer was thoroughly washed with water, dried at about30° C. under reduced pressure. After final purification up to negativetest on p-nitrophenol and p-toluenesulfonic acid (see below), yield is94%, η_(red)=1.40 dL/g. Biodegradation (weight loss in %) at 37° C.after 120 h in phosphate buffer (pH 7.4): ˜0% in pure buffer, 10% in thebuffer with α-chymotrypsin (4 mg/10 mL of buffer), and 35% in the bufferwith lipase (4 mg/10 mL of buffer).

Example 4

[0304] Preparation ofco-poly-{[N,N′-sebacoyl-bis-(L-leucine)-1,6-hexylenediester]}_(0.50)-[N,N′-sebacoyl-(bis-(L-phenylalanine)-1,6-hexylenediester]_(0.25)-{[N,N′-sebacoyl-L-lysine benzyl ester]_(0.25)} (4)(compound of formula (VII) wherein m¹=0.50, m²=0.25, p=0.25, R₁=(CH₂)₈,R₂=Bz, R₃=iso-propyl, and R₄=(CH₂)₆).

[0305] Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixtureof the of di-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylenediester (III, R⁴=(CH₂)₆) (34.446 g, 0.050 mole), thedi-p-toluenesulfonic acid salt of bis-(L-phenylalanine)1,6-hexylenediester (III, R⁴=CH₂Ph) (18.924 g, 0.025 mole), the di-p-toluenesulfonicacid salt of L-lysine benzyl ester (IV) (14.518 g, 0.025 mole) (totalamount of (III)+(IV)=0.1 mole), and di-p-nitrophenyl sebacinate (V,R₁=CH₂)₈) (44.444 g, 0.1 mole) in dry N,N-dimethylacetamide (DMA) (52.5mL) (total volume of DMA and NEt₃ is 83.3 mL, concentration 1.2 mol/L by(III)+(IV) or by (V)) at room temperature. Afterwards, the temperatureof the reaction mixture was increased to about 80° C. and stirred forabout 16 hours. The viscous reaction solution was cooled to roomtemperature, diluted with ethanol (150 mL), and poured into water. Theseparated polymer was thoroughly washed with water, dried at about 30°C. under reduced pressure. After final purification up to negative teston p-nitrophenol and p-toluenesulfonic acid (see below) yield is 95%,η_(red)=0.77 dL/g. Tg=20.6° C. (DSC).

Example 5

[0306] Preparation ofco-poly-{[N,N′-adipoyl-bis-(L-leucine)-1,6-hexylenediester]}_(0.50)-{[N,N′-adipoyl-L-lysine benzyl ester]_(0.50)} (5)(compound of formula (VII) wherein m=0.50, p=0.50, R₁=((CH₂))₄, R₂=Bz,R₃=iso-propyl, and 4=(CH₂)).

[0307] Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixtureof the di-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylenediester (III, R⁴=(CH₂)₆) (34.446 g, 0.050 mole), thedi-p-toluenesulfonic acid salt of L-lysine benzyl ester (V) (29.036 g,0.050 mole) (total amount of (III)+(IV)=0.1 mole), and di-p-nitrophenyladipate (V, R¹=(CH₂)₄) (38.833 g, 0.1 mole) in dry N,N-dimethylacetamide(DMA) (52.5 mL) (total volume of DMA and NEt₃ is 83.3 mL, concentration1.2 mol/L by (III)+(IV) or by (V)) at room temperature. Afterwards, thetemperature of the reaction mixture was increased to about 80° C. andstirred for about 16 hours. The viscous reaction solution was cooled toroom temperature, diluted with ethanol (150 mL), and poured into water.The separated polymer was thoroughly washed with water, dried at about30° C. under reduced pressure. After final purification up to negativetest on p-nitrophenol and p-toluenesulfonic acid (see below) yield is93%, η_(red)=1.25 dL/g.

Example 6

[0308] Preparation ofco-poly-{[N,N′-sebacoyl-bis-(L-leucine)-1,6-hexylenediester]}_(0.50)-{[N,N′-sebacoyl-L-lysine benzyl ester]_(0.50)} (6)(compound of formula (VII) wherein m=0.50, p=0.50, R₁=(CH₂)₈, R₂=Bz,R₃=iso-propyl, and R₄=(CH₂)₆).

[0309] Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixtureof the di-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylenediester (E, R⁴=(CH₂)₆) (34.446 g, 0.050 mole), the di-p-toluenesulfonicacid salt of L-lysine benzyl ester (IV) (29.036 g, 0.050 mole) (totalamount of (III)+(IV)=0.1 mole), and di-p-nitrophenyl sebacinate (V,R¹=(CH₂)₈ (44.444 g, 0.1 mole) in dry N,N-dimethylacetamide (DMA) (52.5mL) (total volume of DMA and NEt₃ is 83.3 mL, concentration 1.2 mol/L by(III)+(IV) or by (V)) at room temperature. Afterwards, the temperatureof the reaction mixture was increased to about 80° C. and stirred forabout 16 hours. The viscous reaction solution was cooled to roomtemperature, diluted with ethanol (150 mL), and poured into water. Theseparated polymer was thoroughly washed with water, dried at about 30°C. under reduced pressure. After final purification up to negative teston p-nitrophenol and p-toluenesulfonic acid (see below) yield is 95%,η_(red)=1.31 dL/g.

Example 7

[0310] Preparation of co-poly-{[N,N′-adipoyl-bis-(L-leucine)1,8-octylenediester]}_(0.90)-{[N,N′-adipoyl-L-lysine benzyl ester]_(0.10)} (7)(compound of formula (VII) wherein m=0.90, p=0.10, R₁=(CH₂)₄, R₂=Bz,R₃=iso-propyl, and R₄=(CH₂)₈).

[0311] Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixtureof the di-p-toluenesulfonic acid salt of bis-(L-leucine)-1,8-octylenediester (III, R⁴=(CH₂)₈) (64.526 g, 0.090 mole), thedi-p-toluenesulfonic acid salt of L-lysine benzyl ester (IV) (5.807 g,0.010 mole) (total amount of (III)+(IV)=0.1 mole), and di-p-nitrophenyladipate (V, R¹=(CH₂)₄) (38.833, 0.1 mole) in dry N,N-dimethylacetamide(DMA) (52.5 mL) (total volume of DMA and NEt₃ is 83.3 mL, concentration1.2 mol/L by (III)+(IV) or by (V)) at room temperature. Afterwards, thetemperature of the reaction mixture was increased to about 80° C. andstirred for about 16 hours. The viscous reaction solution was cooled toroom temperature, diluted with ethanol (150 mL), and poured into water.The separated polymer was thoroughly washed with water, dried at about30° C. under reduced pressure. After final purification up to negativetest on p-nitrophenol and p-toluenesulfonic acid (see below) yield is94%, η_(red)=1.21 dL/g.

Example 8

[0312] Preparation ofco-poly-{[N,N′-sebacoyl-bis-(L-leucine)-1,4-butylenediester]}_(0.09)-{[N,N′-sebacoyl-L-lysine benzyl ester]_(0.10)} (8)(compound of formula (Vet) wherein m=0.90, p=0.10, R₁=(CH₂)₈, R₂=Bz,R₃=iso-propyl, and R₄ (CH₂₎ ₄).

[0313] Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixtureof the di-p-toluenesulfonic acid salt of bis-(L-leucine)-1,4-butylenediester (III, R⁴=(CH₂)₄) (59.477 g, 0.090 mole), thedi-p-toluenesulfonic acid salt of L-lysine benzyl ester (IV) (5.807 g,0.010 mole) (total amount of (III)+(IV)=0.1 mole), and di-p-nitrophenylsebacinate (V, R¹=(CH₂)₈) (44.444 g, 0.1 mole) in dry N,N-imethylacetamide (DMA) (52.5 mL of) (total volume of DMA and NEt₃ is83.3 mL, concentration 1.2 mol/L by (III)+(IV) or by (V)) at roomtemperature. Afterwards, the temperature of the reaction mixture wasincreased to about 80° C. and stirred for about 16 hours. The viscousreaction solution was cooled to room temperature, diluted with ethanol(150 mL), and poured into water. The separated polymer was thoroughlywashed with water, dried at 30° C. under reduced pressure. After finalpurification up to negative test on p-nitrophenol and p-toluenesulfonicacid (see below) yield is 95%, η_(red)=1.28 dL/g.

Example 9

[0314] Preparation ofco-poly-{[N,N′-sebacoyl-bis-(L-leucine)-1,6-hexylenediester])}_(0.90)-{[N,N′-sebacoyl-L-lysine benzyl ester]_(0.10)} (9)(compound of formula (VII) wherein m=0.90, p=0.10, R₁=(CH₂)₈, R₂=Bz,R₃=iso-propyl, and R₄=(C₂)₆).

[0315] Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixtureof the di-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylenediester (III, R⁴=(CH₂)₆) (62.002 g, 0.090 mole), thedi-p-toluenesulfonic acid salt of L-lysine benzyl ester (IV) (5.807 g,0.010 mole) (total amount of (III)+(IV)=0.1 mole), and di-p-nitrophenylsebacinate (V, R¹=(C₂)₈) (44.444 g, 0.1 mole) in dryN,N-dimethylacetamide (DMA) (52.5 mL) (total volume of DMA and NEt₃ is83.3 mL, concentration 1.2 mol/L by (III)+(IV) or by (V)) at roomtemperature. Afterwards, the temperature of the reaction mixture wasincreased to about 80° C. and stirred for about 16 hours. The viscousreaction solution was cooled to room temperature, diluted with ethanol(150 mL), and poured into water. The separated polymer was thoroughlywashed with water, dried at about 30° C. under reduced pressure. Afterfinal purification up to negative test on p-nitrophenol andp-toluenesulfonic acid (see below) yield is 96%, η_(red)=1.41 dL/g.Biodegradation (weight loss in %) at 37° C. after 120 h in phosphatebuffer (pH 7.4): ˜0% in pure buffer, 12% in the buffer withα-chymotrypsin (4 mg/10 mL of buffer), and 38% in the buffer with lipase(4 mg/10 mL of buffer).

Example 10

[0316] Preparation ofco-poly-{[N,N′-sebacoyl-bis-(L-leucine)-1,8-octylenediester]}_(0.90)-{[N,N′-sebacoyl-L-lysine benzyl ester]_(0.10)} (10)(compound of formula (VI) wherein m=_(0.90), p=_(0.10), R₁=(CH₂)₈,R₂=Bz, R₃=iso-propyl, and R₄=(C₂)₈.

[0317] Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixtureof the di-p-toluenesulfonic acid salt of bis-(L-leucine)-1,8-octylenediester (III, R⁴=(CH₂)₈) (64.526 g, 0.090 mole), thedi-p-toluenesulfonic acid salt of L-lysine benzyl ester (IV) (5.807 g,0.010 mole) (total amount of (III)+(IV)=0.1 mole), and di-p-nitrophenylsebacinate (V, R¹=(CH₂)₈) (44.444 g, 0.1 mole) in dryN,N-dimethylacetamide (DMA) (52.5 mL) (total volume of DMA and NEt₃ is83.3 mL, concentration 1.2 mol/L by (III)+(IV) or by (V)) at roomtemperature. Afterwards, the temperature of the reaction mixture wasincreased to about 80° C. and stirred for about 16 hours. The viscousreaction solution was cooled to room temperature, diluted with ethanol(150 mL), and poured into water. The separated polymer was thoroughlywashed with water, dried at about 30° C. under reduced pressure. Afterfinal purification up to negative test on p-nitrophenol andp-toluenesulfonic acid (see below) yield is 97%, η_(red)=1.50 dL/g. Tg27.5° C. (DSC).

Example 11

[0318] Preparation ofco-poly-{[N,N′-sebacoyl-bis-(L-leucine)-1,12-dodecylenediester]}_(0.90)-{[N,N′-sebacoyl-L-lysine benzyl ester]_(0.10)} (11)(compound of formula (VII) wherein m=0.90, p=0.10, R₁=(CH₂)₈, R₂=Bz,R₃=iso-propyl, and R₄=(CH₂)₁₂).

[0319] Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixtureof the di-p-toluenesulfonic acid salt of bis-(L-leucine)-1,12-dodecylenediester (III, R⁴=(CH₂)12) (69.576 g, 0.090 mole), thedi-p-toluenesulfonic acid salt of L-lysine benzyl ester (IV) (5.807 g,0.010 mole) (total amount of (III)+(IV) 0.1 mole), and di-p-nitrophenylsebacinate (V, R¹=(CH₂)₈) (44.444 g, 0.1 mole) in dryN,N-dimethylacetamide (DMA) (52.5 mL) (total volume of DMA and NEt₃ is83.3 mL, concentration 1.2 mol/L by (III)+(IV) or by (V)) at roomtemperature. Afterwards, the temperature of the reaction mixture wasincreased to about 80° C. and stirred for about 16 hours. The viscousreaction solution was cooled to room temperature, diluted with ethanol(150 mL), and poured into water. The separated polymer was thoroughlywashed with water, dried at about 30° C. under reduced pressure. Afterfinal purification, yield is 96% up to negative test on p-nitrophenoland p-toluenesulfonic acid (see below), η_(red)=0.68 dL/g.

Example 12

[0320] Preparation ofco-poly-{[N,N′-dodecyldicarboxyloyl-bis-(L-leucine)-1,6-hexylenediester]}_(0.90)-{[N,N′-dodecyldicarboxyloyl-L-lysine benzylester]_(0.10)} (12) (compound of formula (VII) wherein m=0.90, p=0.10,R₁=(CH₂)₁₂, R₂=Bz, R₃=iso-propyl, and R₄=(CH₂)₆).

[0321] Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixtureof the di-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylenediester (III, R⁴=(CH₂)₆) (62.002 g, 0.090 mole), thedi-p-toluenesulfonic acid salt of L-lysine benzyl ester (IV) (5.807 g,0.010 mole) (total amount of (III)+(IV)=0.1 mole), and di-p-nitrophenyldodecyldicarboxylate (V, R¹=(CH₂)₁₂)(50.055 g, 0.1 mole) in dryN,N-dimethylacetamide (DMA) (52.5 mL) (total volume of DMA and NEt₃ in83.3 mL, concentration 1.2 mol/L by (III)+(IV) or by (V)) at roomtemperature. Afterwards the temperature of the reaction mixture wasincreased to about 80° C. and stirred for about 16 hours. The viscousreaction solution was cooled to room temperature, diluted with ethanol(150 mL), and poured into water. The separated polymer was thoroughlywashed with water, dried at 30° C. under reduced pressure. After finalpurification yield is 96% up to negative test on p-nitrophenol andp-toluenesulfonic acid (see below), η_(red)=1.18 dL/g.

[0322] Preparation of Co-PEURs:

Example 13

[0323] Preparation ofco-poly-{[N,N′-trimethylenedioxydicarbonyl-bis-(L-leucine)1,4-butylenediester]}_(0.75)-{[N,N′-trimethylenedioxydicarbonyl-L-lysine benzylester]_(0.25)} (13) (compound of formula (XI) wherein m=0.75, p=0.25,R₂=Bz, R₃=iso-propyl, R₄=(CH₂)₄), and R₆=(CH₂)₃.

[0324] Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixtureof the di-p-toluenesulfonic acid salt of bis-(L-leucine)-1,4-butylenediester ([H, R⁴═(CH₂)₄) (49.565 g, 0.075 mole), the di-p-toluenesulfonicacid salt of L-lysine benzyl ester (V) (14.518 g, 0.025 mole) (totalamount of (III)+(IV)=0.1 mole), and active bis-carbonate (X) (R⁶=(CH₂)₃(40.624 g, 0.1 mole) in dry N,N-dimethylacetamide DMA) (52.5 mL) (totalvolume of DMA and NEt₃ in 83.3 mL, concentration 1.2 mol/L by (III)+(IV)or by (X)) at room temperature. Afterwards, the temperature of thereaction mixture was increased to about 80° C. and stirred for about 16hours. The viscous reaction solution was cooled to room temperature, andpoured into water. The separated polymer was thoroughly washed withwater, dried at 30° C. under reduced pressure. After final purificationup to negative test on p-nitrophenol and p-toluenesulfonic acid (seebelow) yield is 63%, η_(red)=0.32 dL/g.

Example 14

[0325] Preparation ofco-poly-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)bis-(L-leucine)-1,4-butylenediester]}_(0.75)-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)-L-lysinebenzyl ester]_(0.25)} (14) (compound of formula (XI) wherein m=0.75,p=0.25, R₂=Bz, R₃=iso-propyl, R₄=(CH₂)₄), and R₆=(CH₂)₂—O—(CH₂)₂)

[0326] Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixtureof the di-p-toluenesulfonic acid salt of bis-(L-leucine)-1,4-butylenediester (III, R⁴=(CH₂)₄) (49.565 g, 0.075 mole), thedi-p-toluenesulfonic acid salt of L-lysine benzyl ester (IV) (14.518 g,0.025 mole) (total amount of (III)+(IV)=0.1 mole), and activebis-carbonate (X) (R⁶=(CH₂)₂—O—(CH₂)₂) (43.633 g, 0.1 mole) in dryN,N-dimethylacetamide (DMA) (52.5 mL) (total volume of DMA and NEt₃ is83.3 mL, concentration 1.2 mol/L by (III)+(IV) or by (X)) at roomtemperature. Afterwards, the temperature of the reaction mixture wasincreased to about 80° C. and stirred for about 16 hours. The viscousreaction solution was cooled to room temperature, and poured into water.The separated polymer was thoroughly washed with water, dried at about30° C. under reduced pressure. After final purification up to negativetest on p-nitrophenol and p-toluenesulfonic acid (see below) yield is78%, η_(red)=0.58 dL/g. Biodegradation (weight loss in %) at 37° C.after 240 h in phosphate buffer (pH 7.4): 4.7% in pure buffer, 2.2% inthe buffer with α-chymotrypsin (4 mg/10 mL of buffer), 4.4% in thebuffer with lipase (4 mg/10 mL of buffer). Films with d=4 cm andm=500±50 mg on Teflon backing.

Example 15

[0327] Preparation ofco-poly-{[N,N′-trimethylenedioxydicarbonyl-bis-(L-leucine)-1,6-hexylenediester]}_(0.75)-{[N,N′-trimethylenedioxydicarbonyl-L-lysine benzylester]_(0.25)} (15) (compound of formula (XI) wherein m=0.75, p=0.25,n=112, R₂=Bz, R₃=iso-propyl, R₄=(CH₂)₆, and R₄=(CH₂)₃.

[0328] Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixtureof the di-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylenediester (III, R⁴=(CH₂)₆ (51.668 g, 0.075 mole), the di-p-toluenesulfonicacid salt of L-lysine benzyl ester (IV) (14.518 g, 0.025 mole) (totalamount of (III)+(IV)=0.1 mole), and active bis-carbonate (X) (R⁶=(CH₂)₃)(40.624 g, 0.1 mole) in dry N,N-dimethylacetamide (DMA) (52.5 mL) (totalvolume of DMA and NEt₃ is 83.3 mL, concentration 1.2 mol/L by (III)+(IV)or by (X)) at room temperature. Afterwards, the temperature of thereaction mixture was increased to about 80° C. and stirred for about 16hours. The viscous reaction solution was cooled to room temperature, andpoured into water. The separated polymer was thoroughly washed withwater, dried at about 30° C. under reduced pressure. After finalpurification up to negative test on p-nitrophenol and p-toluenesulfonicacid (see below) yield is 60%, η_(red)=0.53 dL/g. Mw=50,000, Mn=29,900,M_(w)/M_(n)=1.68 (GPC). Biodegradation (weight loss in %) at 37° C.after 180 h in phosphate buffer (pH 7.4): 5.0% in pure buffer, 7.3% inthe buffer with α-chymotrypsin (4 mg/10 mL of buffer), and 8.2% in thebuffer with lipase (4 mg/10 mL of buffer). Films with d=4 cm andm=500±50 mg on Teflon backing.

Example 16

[0329] Preparation ofco-poly-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)-bis-(L-leucine)-1,6-hexylenediester]}_(0.75)-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)L-lysinebenzyl ester]_(0.25)} (16) (compound of formula (XI) wherein m=0.75,p=0.25, n=130, R₂=Bz, R₃=iso-propyl, R₄=(CH₂)₆), and R₆=(CH₂)₂—O—(CH₂)₂)

[0330] Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixtureof the di-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylenediester (III, R⁴=(CH₂)₆) (51.668 g, 0.075 mole), thedi-p-toluenesulfonic acid salt of L-lysine benzyl ester (IV) (14.518 g,0.025 mole) (total amount of (III)+(IV)=0.1 mole), and activebis-carbonate (X) (R⁶=(CH₂)₂—O—(CH₂)₂) (43.633 g, 0.1 mole) in dryN,N-dimethylacetamide (DMA) (52.5 mL) (total volume of DMA and NEt₃ is83.3 mL, concentration 1.2 mol/L by (III)+(IV) or by (X)) at roomtemperature. Afterwards, the temperature of the reaction mixture wasincreased to about 80° C. and stirred for about 16 hours. The viscousreaction solution was cooled to room temperature, and poured into water.The separated polymer was thoroughly washed with water, dried at about30° C. under reduced pressure. After final purification up to negativetest on p-nitrophenol and p-toluenesulfonic acid (see below) yield is68%, η_(red)=0.72 dL/g. Mw=61,900, n=38,500, Mw/Mn=1.61 (GPC).Biodegradation (weight loss in %) at 37° C. after 180 h in phosphatebuffer (pH 7.4): 4.0% in pure buffer, 5.6% in the buffer withα-chymotrypsin (4 mg/10 mL of buffer), and 8.9% in the buffer withlipase (4 mg/10 mL of buffer). Films with d=4 cm and m=500±50 mg onTeflon backing.

Example 17

[0331] Preparation ofco-poly-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)-bis-(L-leucine)-1,6-hexylenediester]}_(0.50)-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)-L-lysinebenzyl ester]_(0.50)} (17) (compound of formula (XI) wherein m=0.50,p=0.50, n=85, R₂=Bz, R₃=iso-propyl, R₄=(CH₂)₆), and R₆=(CH₂)₂—O—(CH₂)₂).

[0332] Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixtureof di-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylenediester (III, R⁴=(CH₂)₆) (34.446 g, 0.050 mole), thedi-p-toluenesulfonic acid salt of L-lysine benzyl ester (IV) (29.036 g,0.050 mole) (total amount of (III)+(IV)=0.1 mole), and activebis-carbonate (X) (R⁶=(CH₂)₂—O—(CH₂)₂) (43.633 g, 0.1 mole) in dryN,N-dimethylacetamide (DMA) (52.5 mL) (total volume of DMA and NEt₃ is83.3 mL, concentration 1.2 mol/L by (III)+(IV) or by (X)) at roomtemperature. Afterwards, the temperature of the reaction mixture wasincreased to about 80° C. and stirred for about 16 hours. The viscousreaction solution was cooled to room temperature, and poured into water.The separated polymer was thoroughly washed with water, dried at about30° C. under reduced pressure. After final purification up to negativetest on p-nitrophenol and p-toluenesulfonic acid (see below) yield is80%, η_(red)=0.45 dL/g. M_(w)=37,900, M_(n)=22,300, Mw/Mn=1.70 (GPC).

Example 18

[0333] Preparation ofco-poly-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)-bis-(L-leucine)-1,6-hexylenediester]}_(0.90)-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)-L-lysinebenzyl ester]_(0.10)} (18) (compound of formula (XI) wherein m=0.90,p=0.10, n=115, R₂=Bz, R₃=iso-propyl, R₄=(CH₂)₆), and R₆=(C₂)₂—O—(CH₂)₂).

[0334] Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixtureof the di-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylenediester (III, R⁴=(CH₂)₆) (62.002 g, 0.090 mole), thedi-p-toluenesulfonic acid salt of L-lysine benzyl ester (IV) (5.807 g,0.025 mole) (total amount of (III)+(IV)=0.1 mole), and activebis-carbonate (X) (R⁶=(CH₂)₂—O—(CH₂)₂) (43.633 g, 0.1 mole) in dryN,N-dimethylacetamide (DMA) (52.5 mL) (total volume of DMA and NEt₃ is83.3 mL, concentration 1.2 mol/L by (III)+(IV) or by (X)) at roomtemperature. Afterwards, the temperature of the reaction mixture wasincreased to about 80° C. and stirred for about 16 hours. The viscousreaction solution was cooled to room temperature, and poured into water.The separated polymer was thoroughly washed with water, dried at about30° C. under reduced pressure. After final purification up to negativetest on p-nitrophenol and p-toluenesulfonic acid (see below) yield is70%, η_(red)=0.74 dL/g. M_(w)=56,500, M_(n)=33,700, M_(w)/M_(n)=1.68(GPC).

Example 19

[0335] Preparation ofco-poly-{[N,N′-trimethylenedioxydicarbonyl-bis-(L-leucine)-1,8-octylenediester]}_(0.75)-{N,N′-trimethylenedioxydicarbonyl-L-lysine benzylester]_(0.25)} (19) (compound of formula (XI) wherein m=0.75, p=0.25,R₂=Bz, R₃=iso-propyl, R₄=(CH₂)₈), and R₆=(CH₂)₃.

[0336] Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixtureof the di-p-toluenesulfonic acid salt of bis-(L-leucine)-1,8-octylenediester (III, R⁴=(CH₂)₈) (53.772 g, 0.075 mole), thedi-p-toluenesulfonic acid salt of L-lysine benzyl ester (IV) (14.518 g,0.025 mole) (total amount of (III)+(IV)=0.1 mole), and activebis-carbonate (X) (R⁶=(CH₂₎ ₃) (40.624 g, 0.1 mole) in dryN,N-dimethylacetamide DMA) (52.5 mL) (total volume of DMA and NEt₃ is83.3 mL, concentration 1.2 mol/L by (III)+(IV) or by (X)) at roomtemperature. Afterwards, the temperature of the reaction mixture wasincreased to about 80° C. and stirred for about 16 hours. The viscousreaction solution was cooled to room temperature, and poured into water.The separated polymer was thoroughly washed with water, dried at about30° C. under reduced pressure. After final purification up to negativetest on p-nitrophenol and p-toluenesulfonic acid (see below) yield is84%, η_(red)=0.46 dL/g. Biodegradation (weight loss in %) at 37° C.after 240 h in phosphate buffer (pH 7.4): 0.9% in pure buffer, 2.0% inthe buffer with a-chymotrypsin (4 mg/10 mL of buffer), and 3.7% in thebuffer with lipase (4 mg/0 mL of buffer). Films with d=4 cm and m=500±50mg on Teflon backing.

Example 20

[0337] Preparation ofco-poly-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)-bis-(L-leucine)-1,8-octylenediester]}_(0.75)-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)-L-lysinebenzyl ester]_(0.25)} (20) (compound of formula (XI) wherein m=0.75,p=0.25, R₂=Bz, R₃=iso-propyl, R₄=(CH₂)₈), and R₆=(CH₂)₂—O—(CH₂)₂).

[0338] Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixtureof the di-p-toluenesulfonic acid salt of bis-(L-leucine)-1,8-octylenediester (III, R₄=(CH₂)₈) (53.772 g, 0.075 mole), thedi-p-toluenesulfonic acid salt of L-lysine benzyl ester (IV) (14.518 g,0.025 mole) (total amount of (III)+(IV)=0.1 mole), and activebis-carbonate (X) R⁶=(CH₂)₂—(CH₂)(43.63 g, 0.1 mole) in dryN,N-dimethylacetamide (DMA) (52.5 mL) (total volume of DMA and NEt₃ is83.3 mL, concentration 1.2 mol/L by (III)+(IV) or by (X)) at roomtemperature. Afterwards the temperature of the reaction mixture wasincreased to about 80° C. and stirred for 16 hours. The viscous reactionsolution was cooled to room temperature, and poured into water. Theseparated polymer was thoroughly washed with water, dried at about 30°C. under reduced pressure. After final purification, yield is 76% up tonegative test on p-nitrophenol and p-toluenesulfonic acid (see below),η_(red)=0.42 dL/g.

Example 21

[0339] Preparation ofco-poly-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)-bis-(L-leucine)-1,8-octylenediester]}_(0.90)-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)-L-lysinebenzyl ester]_(0.10)} (21) (compound of formula (XI) wherein m=0.90,p=0.10, R₂=Bz, R₃=iso-propyl, R₄=(CH₂)₈), and R₆=(CH₂)₂—O—(CH₂)₂).

[0340] Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixtureof the di-p-toluenesulfonic acid salt of bis-(L-leucine)-1,8-octylenediester (III, R⁴=(C₂)₈) (64.5264 g, 0.09 mole), the di-p-toluenesulfonicacid salt of L-lysine benzyl ester (IV) (5.8072 g, 0.01 mole) (totalamount of (III)+(IV)=0.1 mole), and active bis-carbonate (X)(R⁶=(CH₂)₂—O—(CH₂)₂) (43.63 g, 0.1 mole) in dry N,N-dimethylacetamide(DMA) (52.5 mL) (total volume of DMA and NEt₃ is 83.3 mL, concentration1.2 mol/L by (III)+(IV) or by (X)) at room temperature. Afterwards thetemperature of the reaction mixture was increased to about 80° C. andstirred for 16 hours. The viscous reaction solution was cooled to roomtemperature, and poured into water. The separated polymer was thoroughlywashed with water, dried at about 30° C. under reduced pressure. Afterfinal purification up to negative test on p-nitrophenol andp-toluenesulfonic acid (see below) yield is 63%, η_(red)=0.51 dL/g.

Example 22 Deprotection of Polymeric Benzyl Esters (General Procedure)

[0341] According to the general procedure described herein for thepreparation of coPEAs and coPEURs, the polymers were obtained as thebenzyl ester forms. For the preparation of the corresponding polymershaving free COOH groups, these polymers having the benzyl esters weresubjected to catalytic debenzylation using hydrogen (H₂) gas andpalladium (Pd) black as a catalyst. Suitable reaction conditions areavailable, e.g., in T. W. Greene, Protecting Groups In OrganicSynthesis; Wiley: New York, 1981; J. March, Advanced Organic Chemistry.Reactions, Mechanisms and Structure, (2nd Ed.), McGraw Hill: New York,1977; F. Carey and R. Sundberg, Advanced Organic Chemistry Part B:Reactions and Synthesis, (2nd Ed.), Plenum: New York, 1977; andreferences cited therein.

[0342] (A.) Deprotection of Polymeric Benzyl Esters (coPEAs)

[0343] Palladium black catalyst (3.0 g) was added to a solution of thepolymer (benzyl ester form) (10 g) in ethanol (100 mL), and dry gaseoushydrogen was bubbled through the solution for about 10 hours to about 20hours. A magnetic stirrer was used to agitate the solution. Aftercatalytic hydrogenolysis was complete, the reaction mixture wasfiltered, and clear and colorless solutions were obtained.

[0344] (B.) Deprotection of Polymeric Benzyl Esters (coPEURs)

[0345] Palladium black catalyst (3.0 g) was added to a solution of thepolymer (benzyl ester form) (10 g) in ethyl acetate (100 mL), and drygaseous hydrogen was bubbled through the solution for about 10 hours toabout 30 hours. A magnetic stirrer was used to agitate the solution.After catalytic hydrogenolysis was complete, the reaction mixture wasfiltered, and clear and colorless solutions were obtained

[0346] After deprotection of the polymers, no substantial change ofmolecular weight or polydispersity was observed. For example, for thecompound (2) from Table 3 (i.e., benzyl ester form) the molecular weightcharacteristics were as follows: Mw=31.300, Mn=21.000, Mw/Mn=1.49. Afterhydrogenolysis, molecular weight characteristics are: Mw=40.900,Mn=28.000, and Mw/M_(n)=1.46.

Example 23 Purification of the Benzyl Ester Polymers (GeneralProcedures)

[0347] After the polymers were precipitated in water and thoroughlywashed with water, the solvent (DMA) and p-toluenesulfonic acid salt oftriethylamine were removed (nearly to completion). However, the polymersstill contain a significant amount of by-product of the polycondensation(e.g., p-nitrophenol) which was removed as described below.

[0348] (A.) Purification of coPEAs

[0349] The polymer obtained above (10 g) was dissolved in ethanol (50mL, 95%). The solution was filtered and the polymer was precipitated inethyl acetate (1.0 L), where it separates as tar like mass, and was keptovernight in refrigerator. The ethyl acetate was removed and a freshportion of ethyl acetate (1.0 L) was added to the tar like mass and keptovernight in refrigerator again. This procedure was repeated until anegative test on p-nitrophenol (see below) was obtained. Normally it wasrepeated for 1-2 times. After such a treatment, p-nitrophenol (which ismore soluble in ethylacetate than in water), was nearly completelyremoved from the polymers. The obtained tar like mass was dried,dissolved in 95% ethanol, precipitated in distilled water as arubber-like mass, and dried at about 60° C. under reduced pressure.Yields of purified coPEAs were up to about 97%.

[0350] (B.) Purification of coPEURs

[0351] The polymer obtained above (10 g) was dissolved in chloroform(100 mL), cast as a thin film onto a cylindrical glass vessel's(d=400-500 mm) inner surface, dried at room temperature, thoroughlywashed with water, and dried again. The film obtained was dissolved indimethylformamide (DMF), and the polymer was precipitated in water. Arubber-like polymer was collected and dried at about 35° C. to about 40°C. under reduced pressure. This procedure was repeated for severaltimes, until a negative test on p-nitrophenol was obtained (see below).Normally it was repeated about 3-4 times. After such a treatment, theyields of coPEURs decreased to ≦80%, however the viscosities increased,which is believed to be the result of the loss of low-molecular-weightfractions.

[0352] (C.) Purification of Deprotected Polymers (Polyacids)

[0353] After deprotection, polymers were purified by precipitation froman ethanol solution in water. A rubber-like mass was collected and driedat room temperature under reduced pressure. Example 25

4-AminoTEMPO Attachment and its Biodegradation and Free Radicals ReleaseStudy

[0354] For this study the co-PEA of the following structure was chosen:

[0355] (The hydrogenolysis product of the Example 2) which revealedexcellent elasticity (elongation at break ca. 1000%) and was used in invivo “stent experiments”.

[0356] 4-AminoTEMPO (TAM) was attached to this polyacid usingcarbonyldiimidazol (Im₂CO) as a condensing agent. In typical procedure 1g of polyacid was dissolved in 10 mL of purified, freshly distilledchloroform. A molar equivalent of carbonyldiimidazole was added at roomtemperature and stirred. A molar equivalent of TAM was added, stirredfor 4 h, and kept at r. t. overnight. The solution was filtered and castonto a hydrophobic surface. Chloroform was evaporated to dryness. Theobtained film was thoroughly washed with distilled water and dried underreduced pressure at r.t. An elastic, light red-brown film was obtained.The degree of TAM attachment was 90-95%, determined by UVspectrophotometry in ethanol solution at 250 nm (Polymer does not absorbat this wavelength).

[0357] After TAM attachment, the polymer retained elastic properties. Itdegraded by lipase according to nearly zero order biodegradationkinetics (that is ideal for drug controlled release devices) whileretaining the film's integrity whereas the starting polyacid completelydegraded and/or disintegrated within 48 h in slightly alkaline buffersolution in the presence of lipase). TAM attached polymer is designatedas GJ-2(TAM).

[0358] For the biodegradation study, the film of GJ-2(TAM) was obtained,it was dissolved in 10 mL of chloroform, and a Teflon disk of d=4 cm wascovered by this solution for several times and evaporated so that theweight of dried polymeric coating was ca. 500 mg. The disc was placed ina lipase solution (4 mg of the enzyme in 10 mL of phosphate buffer withpH 7.4. 6 mL of the enzyme was dissolved in 15 mL of the buffer—10 mLwas used for biodegradation experiment, 5 mL—for the compensation in UVmeasurements) and placed in thermostat at 37° C. The enzyme solution waschanged every 24 h. Every 24 h the film was removed, dried with filerpaper and weighed. The buffer solution was analyzed by UV-spectroscopyat 250 nm since the polymeric degradation products don't absorb at thiswavelength. The same solution of the enzyme was used for thecompensation.

[0359] The obtained results indicate that both biodegradation (weightloss) of the polymer and TAM releasing are very close to zero orderkinetics.

[0360] Since the amide bond through which the TAM is attached to thepolymer is rather stable under the biodegradation conditions, it isexpected that TAM is released to the polymeric debris. At the same timethe calibration curve of TAM in buffer was used for quantitativemeasurements. Therefore, the amount of TAM (in mg), determined byUV-spectroscopy, corresponds to the free TAM in mg (in mg/equivalent).

[0361] After 216 h (9 days) biodegradation polymer lost Ca. 11% of theweight, and ca. 8% of the attached TAM was released This, along withbiodegradation and TAM releasing profiles, indicates that the TAMreleasing is determined by the erosion of the polymeric film.

[0362] The results of the biodegradation (weight loss in mg/cm²) of4-AminoTEMPO (TAM), attached to a co-PEA of the present invention, andthe linetics of nitroxyl radical release from 4-AminoTEMPO (TAM),attached to a co-PEA of the present invention, are shown in the chartsbelow. Chart 1 illustrates the biodegradation (weight loss in mg/cm²) ofAmino TEMPO (TAM) attached to a representative compound of the presentinvention. Chart 2 illustrates the kinetics of nitroxyl radical releasefrom 4-Amino TEMPO (TAM) attached to a representative compound of thepresent invention.

Example 24 Test on Purity (General Procedure)

[0363] The coPEA or coPEUR (200-250 mg) was dissolved in a boiling 10%water solution of NaOH (5.0 mL), and the resulting solution was analyzedusing UV-VIS spectrophotometer (Specord UV-VIS, Carl Zeiss, Jena, cellof 4 mL, 1=1,0 cm). The absence of the absorption in the region of250-280 nm (TosO⁻) and at 430 nm (O₂NC₆H₄O⁻) indicates that neitherp-toluenesulfonic acid nor p-nitrophenol exists in the polymeric sampleto any appreciable degree. It is noted that in alkaline media,p-nitrophenol does not absorb in UV region. As such, its absorption doesnot overlap the absorption of p-toluenesulfonic acid.

[0364] The structure of the benzylated polymers prepared in Examples1-21 is given in the Tables below.

Example 25

[0365] TABLE I (VII)

Compound R₁ R₂ R₃ R₄ m p n  (1) (CH₂)₄ Bz iso-propyl (CH₂)₆ 0.75 0.25 75 (2) (CH₂)₈ Bz iso-propyl (CH₂)₆ 0.75 0.25 65  (3) (CH₂)₄ Bz iso-propyland Bz (CH₂)₆ 0.75(0.50 + 0.25) 0.25 —  (4) (CH₂)₈ Bz iso-propyl (CH₂)₆0.75(0.50 + 0.25) 0.25 —  (5) (CH₂)₄ Bz iso-propyl (CH₂)₆ 0.50 0.50 — (6) (CH₂)₈ Bz iso-propyl (CH₂)₆ 0.50 0.50 —  (7) (CH₂)₄ Bz iso-propyl(CH₂)₈ 0.90 0.10 —  (8) (CH₂)₈ Bz iso-propyl (CH₂)₄ 0.90 0.10 —  (9)(CH₂)₈ Bz iso-propyl (CH₂)₆ 0.90 0.10 — (10) (CH₂)₈ Bz iso-propyl (CH₂)₈0.90 0.10 — (11) (CH₂)₈ Bz iso-propyl _( (CH) ₂)₁₂ 0.90 0.10 — (12)(CH₂)₁₂ Bz iso-propyl (CH₂)₆ 0.90 0.10 —

Example 26

[0366] TABLE II (XI)

Compound R₂ R₃ R₄ R₆ m p n (13) Bz iso-propyl (CH₂)₄ (CH₂)₃ 0.75 0.25 —(14) Bz iso-propyl (CH₂)₄ (CH₂)₂—O—(CH₂)₂ 0.75 0.25 — (15) Bz iso-propyl(CH₂)₆ (CH₂)₃ 0.75 0.25 112 (16) Bz iso-propyl (CH₂)₆ (CH₂)₂—O—(CH₂)₂0.75 0.25 130 (17) Bz iso-propyl (CH₂)₆ (CH₂)₂—O—(CH₂)₂ 0.50 0.50  85(18) Bz iso-propyl (CH₂)₆ (CH₂)₂—O—(CH₂)₂ 0.90 0.10 115 (19) Bziso-propyl (CH₂)₈ (CH₂)₃ 0.75 0.25 — (20) Bz iso-propyl (CH₂)₈(CH₂)₂—O—(CH₂)₂ 0.75 0.25 — (21) Bz iso-propyl (CH₂)₈ (CH₂)₂—O—(CH₂)₂0.90 0.10 —

[0367] The physical properties of the polymers prepared in Examples 1-12are given in Table III.

Example 27

[0368] TABLE III Mw/Mn (GPC B.W.L. Tg Compound Yield (%) η_(red) (dL/g)Mw Mn in THF) B.W.L. (%)¹ B.W.L. (%)² (%)³ (DSC) (1) 90 1.30 32,10027,000 1.19 (2) 91 1.40 31,300 21,000 1.49 ˜0 1-2 1-2 (3) 94 1.40 ˜0 1035 (4) 95 0.77 20.6° C. (5) 93 1.25 (6) 95 1.31 (7) 94 1.21 (8) 95 1.28(9) 96 1.41 ˜0 12 38 (10) 97 1.50 27.5° C. (11) 96 0.68 (12) 96 1.18(13) 63 0.32 (14) 78 0.58 4.7⁴ 2.2⁵ 4.4⁶ (15) 60 0.53 50,000 29,900 1.685.0⁷ 7.3⁸ 8.2⁹ (16) 68 0.72 61,900 38,500 1.61 0.4⁷ 5.6⁸ 8.9⁹ (17) 800.45 37,900 22,300 1.70 (18) 70 0.74 56,500 33,700 1.68 (19) 84 0.460.9⁴ 2.0⁵ 3.7⁶ (20) 76 0.42 (21) 63 0.51

[0369] The benzylated polymers obtained had high Mw in the range30,000-60,000 and narrow polydispersity—Mw/Mn=1.2-1.7 (Determined by GPCfor the polymers, soluble in THF), and possess excellent film-formingproperties. They revealed rather low glass transition temperature(Tg=9-20° C.). The polymers are soluble in common organic solvents likechloroform (all of them), ethanol, (copoly(ester amide)s), ethylacetate(copoly(ester urethane)s), some of them in THF. Both co-PEAs andco-PEURs reveal rather high tendency to in vitro biodegradation. Co-PEAsare more inclined to specific (enzyme catalyzed) hydrolysis, whereasco-PEURs showed the tendency to both specific and non-specific(chemical) hydrolysis.

Example 28 In Vitro Biodegradation Study

[0370] In vitro biodegradation studies were performed by weight loss.Standard films with d=4 cm and m=450-550 mg (pure films in case ofnon-contractive poly(ester amide)s and films on Teflon backing in caseof contractive poly(ester urethane)s), were placed into the glassvessels containing 10 mL of 0.2 M phosphate buffer solution with pH=7.4(either pure buffer or buffer containing 4 mg of anenzyme-α-chymotrypsin or lipase) and placed at 37° C. The films wereremoved from the solutions after a predetermined time, dried with filterpaper and weighted. Buffer or enzyme solution was changed every 24 h.

[0371] All publications, patents, and patent documents are incorporatedby reference herein, as though individually incorporated by reference.The invention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

What is claimed is:
 1. A polymer of formula (VII):

wherein m is about 0.1 to about 0.9; p is about 0.9 to about 0.1; n is about 50 to about 150; each R¹ is independently (C₂-C₂₀)alkyl; each R² is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; and each R⁴ is independently (C₂-C₂₀)alkyl.
 2. The polymer of claim 1 wherein each R¹ is independently (CH₂)₄, (CH₂)₈, or (CH₂)₁₂.
 3. The polymer of claim 1 wherein each R² is independently hydrogen or benzyl.
 4. The polymer of claim 1 wherein each R³ is independently isobutyl or benzyl.
 5. The polymer of claim 1 wherein each R⁴ is independently (CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂)₁₂.
 6. The polymer of claim 1 wherein p/(p+m) is about 0.9 to about 0.1.
 7. The polymer of claim 1 wherein m/(p+m) is about 0.1 to about 0.9.
 8. A polymer of formula (VII) comprising one or more subunits of the formula (I):

wherein R¹ is independently (C₂-C₂₀)alkyl; and R² is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; and one or more subunits of the formula (II):

wherein each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; and R⁴ is independently (C₂-C₂₀)alkyl.
 9. The polymer of claim 8 wherein R¹ is independently (CH₂)₄, (CH₂)₈, or (CH₂)₁₂.
 10. The polymer of claim 8 wherein R² is independently hydrogen or benzyl.
 11. The polymer of claim 8 wherein each R³ is independently iso-butyl or benzyl.
 12. The polymer of claim 8 wherein R⁴ is independently (CH₂)₄, (CH₂)₆ (CH₂)₈, or (CH₂)₁₂.
 13. The polymer of claim 8 that is a polymer of formula (VII):

wherein m is about 0.1 to about 0.9; p is about 0.9 to about 0.1; and n is about 50 to about
 150. 14. The polymer of claim 13 wherein p/(p+m) is about 0.9 to about 0.1.
 15. The polymer of claim 13 wherein m/(p+m) is about 0.1 to about 0.9.
 16. A polymer of formula (VD) formed from an amount of one or more compounds of formula (m):

wherein each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; and R⁴ is independently (C₂-C₂₀)alkyl; or a suitable salt thereof; an amount of one or more compounds of formula (IV):

wherein R² is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; or a suitable salt thereof; and an amount of one or more compounds of formula (V):

wherein R¹ is independently (C₂-C₂₀)alkyl; and each R⁵ is independently (C₆-C₁₀)aryl optionally substituted with one or more nitro, cyano, halo, trifluoromethyl or trifluoromethoxy.
 17. The polymer of claim 16 wherein R¹ is independently (CH₂)₄, (CH₂)₈, or (CH₂)₁₂.
 18. The polymer of claim 16 wherein R² is independently hydrogen or benzyl.
 19. The polymer of claim 16 wherein each R³ is independently iso-butyl or benzyl.
 20. The polymer of claim 16 wherein R⁴ is independently (CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂)₁₂.
 21. The polymer of claim 16 wherein each R⁵ is p-nitrophenyl.
 22. The polymer of claim 16 wherein the compound of formula (III) is the di-p-tolunesulfonic acid salt of a bis-(L-α-amino acid)-α,ω-alkylene diester.
 23. The polymer of claim 16 wherein the compound of formula (I) is the di-p-tolunesulfonic acid salt of L-lysine benzyl ester.
 24. The polymer of claim 16 wherein the compound of formula (V) is di-p-nitrophenyl adipate, di-p-nitrophenyl sebacinate, or di-p-nitrophenyl dodecyldicarboxylate.
 25. The polymer of claim 16 that is a polymer of formula (VII):

wherein m is about 0.1 to about 0.9; p is about 0.9 to about 0.1; and n is about 50 to about
 150. 26. The polymer of claim 25 wherein p/(p+m) is about 0.9 to about 0.1.
 27. The polymer of claim 25 wherein m/(p+m) is about 0.1 to about 0.9.
 28. A method for preparing a polymer of formula (VII):

wherein m is about 0.1 to about 0.9; p is about 0.9 to about 0.1; n is about 50 to about 150; each R¹ is independently (C₂-C₂₀)alkyl; each R² is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; and each R⁴ is independently (C₂-C₂₀)alkyl; comprising contacting an amount of one or more compounds of formula (III):

or a suitable salt thereof; an amount of one or more compounds of formula (IV):

or a suitable salt thereof; and an amount of one or more compounds of formula (V):

wherein each R⁵ is independently (C₆-C₁₀)aryl optionally substituted with one or more nitro, cyano, halo, trifluoromethyl, or trifluoromethoxy; under suitable conditions to provide the polymer of formula (VII).
 29. The method of claim 28 wherein each R¹ is independently (CH₂)₄, (CH₂)₈, or (CH₂)₁₂.
 30. The method of claim 28 wherein each R² is independently hydrogen or benzyl.
 31. The method of claim 28 wherein each R³ is independently iso-butyl or benzyl.
 32. The method of claim 28 wherein each R⁴ is independently (CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂)12.
 33. The method of claim 28 wherein each R⁵ is p-nitrophenyl.
 34. The method of claim 28 wherein the compound of formula (III) is the di-p-tolunesulfonic acid salt of a bis-(L-α-amino acid)-α,ω-alkylene diester.
 35. The method of claim 28 wherein the compound of formula (IV) is the di-p-tolunesulfonic acid salt of L-lysine benzyl ester.
 36. The method of claim 28 wherein the compound of formula (V) is di-p-nitrophenyl adipate, di-p-nitrophenyl sebacinate, or di-p-nitrophenyl dodecyldicarboxylate.
 37. The method of claim 28 wherein the contacting is carried out in the presence of a base.
 38. The method of claim 37 wherein the base is triethylamine.
 39. The method of claim 28 wherein the contacting is carried out in the presence of a solvent.
 40. The method of claim 39 wherein the solvent is N,N-dimethylacetamide.
 41. The method of claim 28 wherein the contacting is carried out at about 50° C. to about 100° C.
 42. The method of claim 28 wherein the contacting occurs for about 10 hours to about 24 hours.
 43. The method of claim 28 further comprising purifying the polymer of formula (VII).
 44. The method of claim 28 wherein p/(p+m) is about 0.9 to about 0.1.
 45. The method of claim 28 wherein m/(p+m) is about 0.1 to about 0.9.
 46. A polymer of formula (XI):

m is about 0.91 to about 0.9; p is about 0.9 to about 0.1; n is about 50 to about 150; each R² is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; each R⁴ is independently (C₂-C₂₀)alkyl; and each R⁶ is independently (C₂-C₂₀)alkyl or (C₂-C₈)alkyloxy(C₂-C₂₀)alkyl.
 47. The polymer of claim 46 wherein each R² is independently hydrogen or benzyl.
 48. The polymer of claim 46 wherein each is independently iso-butyl or benzyl.
 49. The polymer of claim 46 wherein each R² is independently (CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂)₁₂.
 50. The polymer of claim 46 wherein each R⁶ is independently (CH₂)₃ or (CH₂)₂—O—(CH₂)₂.
 51. The polymer of claim 46 wherein p/(p+m) is about 0.9 to about 0.1.
 52. The polymer of claim 46 wherein m/(p+m) is about 0.1 to about 0.9.
 53. A polymer of formula (XI) comprising one or more subunits of the formula (VIII):

wherein each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₁₀)alkenyl, (C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; and R⁴ is independently (C₂-C₂₀)allyl; R⁶ is independently (C₂-C₂₀)alkyl or (C₂-C₈)alkyloxy(C₂-C₂₀)alkyl; and one or more subunits of the formula (IX):

wherein R² is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl.
 54. The polymer of claim 53 wherein R² is independently hydrogen or benzyl.
 55. The polymer of claim 53 wherein each R³ is independently iso-butyl or benzyl.
 56. The polymer of claim 53 wherein R⁴ is independently (CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂)₁₂.
 57. The polymer of claim 53 wherein R⁶ is independently (CH₂)₃ or (CH₂)₂—O—(CH₂)₂.
 58. The polymer of claim 53 that is a polymer of formula (XI):

wherein m is about 0.1 to about 0.9; p is about 0.9 to about 0.1; n is about 50 to about 150; each R² is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; each R⁴ is independently (C₂-C₂₀)alkyl; each R⁵ is independently (C₆-C₁₀)aryl optionally substituted with one or more nitro, cyano, halo, trifluoromethyl, or trifluoromethoxy; and each R⁶ is independently (C₂-C₂₀)alkyl or (C₂-C₂₀)alkyloxy(C₂-C₂₀)alkyl.
 59. A polymer of formula (XI) formed from an amount of one or more compounds of formula (III):

wherein each R³ is independently hydrogen, (C₁C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; and R⁴ is independently (C₂-C₂₀)alkyl; or a suitable salt thereof; an amount of one or more compounds of formula (IV):

wherein R² is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; or a suitable salt thereof; and an amount of one or more compounds of formula (X):

wherein each R⁵ is independently (C₆-C₁₀)aryl optionally substituted with one or more nitro, cyano, halo, trifluoromethyl, or trifluoromethoxy; and R⁶ is independently (C₂-C₂₀)alkyl or (C₂-C₈)alkyloxy(C₂-C₂₀)alkyl.
 60. The polymer of claim 59 wherein R² is independently hydrogen or benzyl.
 61. The polymer of claim 59 wherein each R³ is independently iso-butyl or benzyl.
 62. The polymer of claim 59 wherein R⁴ is independently (CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂)₁₂.
 63. The polymer of claim 59 wherein each R⁵ is p-nitrophenyl.
 64. The polymer of claim 59 wherein R⁶ is independently (CH₂)₃ or (CH₂)₂—O—(CH₂)₂.
 65. The polymer of claim 59 wherein the compound of formula (III) is the di-p-tolunesulfonic acid salt of a bis-(Lα-amino acid)-α,ω-alkylene diester.
 66. The polymer of claim 59 wherein the compound of formula (IV) is the di-p-tolunesulfonic acid salt of L-lysine benzyl ester.
 67. The polymer of claim 59 wherein the compound of formula (X) is 1,3-bis (4-nitro-phenoxycarbonyloxy) propane; or 2,2′-bis nitrophenoxycarbonyloxy ethylether.
 68. The polymer of claim 59 that is a polymer of formula (XI):

wherein m is about 0.1 to about 0.9; p is about 0.9 to about 0.1; and n is about 50 to about
 150. 69. The polymer of claim 68 wherein p/(p+m) is about 0.9 to about 0.1.
 70. The polymer of claim 68 wherein m/(p+m) is about 0.1 to about 0.9.
 71. A method for preparing a polymer of formula (XI):

wherein m is about 0.1 to about 0.9; p is about 0.9 to about 0.1; n is about 50 to about 150; each R² is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; each R³ is independently hydrogen, (C₁-C₆)alkyl (C2-C₆)alkenyl (C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; each R⁴ is independently (C₂-C₂₀)alkyl; each R⁵ is independently (C₆-C₁₀)aryl optionally substituted with one or more nitro, cyano, halo, trifluoromethyl, or trifluoromethoxy; and each R⁶ is independently (C₂-C₂₀)alkyl or (C₂-C₈)alkyloxy(C₂-C₂₀)alkyl; comprising contacting an amount of one or more compounds of formula (III):

or a suitable salt thereof; an amount of one or more compounds of formula (IV):

or a suitable salt thereof; and an amount of one or more compounds of formula (X):

under suitable conditions to provide the polymer of formula (X).
 72. The method of claim 71 wherein each R² is independently hydrogen or benzyl.
 73. The method of claim 71 wherein each R³ is independently iso-butyl or benzyl.
 74. The method of claim 71 wherein each R⁴ is independently (CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂)₁₂.
 75. The method of claim 71 wherein each R⁵ is p-nitrophenyl.
 76. The method of claim 71 wherein each R⁶ is independently (CH₂)₃ or (CH₂)₂—O—(CH₂)₂.
 77. The method of claim 71 wherein the compound of formula (III) is the di-p-tolunesulfonic acid salt of a bis(L-α-amino acid)-α,ω-alkylene diester.
 78. The method of claim 71 wherein the compound of formula (IV) is the di-p-tolunesulfonic acid salt of L-lysine benzyl ester.
 79. The method of claim 71 wherein the compound of formula (X) is 1,3-bis (4-nitro-phenoxycarbonyloxy) propane; or 2,2′-bis-4-nitrophenoxycarbonyloxy ethylether.
 80. The method of claim 71 wherein the contacting is carried out in the presence of a base.
 81. The method of claim 80 wherein the base is triethylamine.
 82. The method of claim 71 wherein the contacting is carried out in the presence of a solvent.
 83. The method of claim 82 wherein the solvent is N,N-dimethylacetamide.
 84. The method of claim 71 wherein the contacting is carried out at about 50° C. to about 100° C.
 85. The method of claim 71 wherein the contacting occurs for about 10 hours to about 24 hours.
 86. The method of claim 71 further comprising purifying the polymer of formula (XI).
 87. The method of claim 71 wherein p/(p+m) is about 0.9 to about 0.1.
 88. The method of claim 71 wherein m/(p+m) is about 0.1 to about 0.9.
 89. A method of using a polymer of any one of claims 1-70 for use as a medical device, a pharmaceutical, a carrier for covalent immobilization of a drug, or a bioactive substance.
 90. A method of using a polymer of any one of claims 1-70 for the manufacture of a medical device, a pharmaceutical, a carrier for covalent immobilization of a drug, or a bioactive substance.
 91. A polymer of formula (VII) as recited in any one of claims 1-27, that is linked to one or more drugs.
 92. The polymer of claim 91 wherein a residue of the polymer is linked directly to a residue of the drug.
 93. The polymer of claim 92 wherein the residue of the polymer is linked directly to the residue of the drug through an amide, ester, ether, amino, ketone, thioether, sulfinyl, sulfonyl, disulfide, or a direct linkage.
 94. The polymer of claim 92 wherein the residue of the polymer is linked directly to the residue of the drug through one of the following linkages: —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—, —C(═(O)—, —S—, —S(O)—, —S(O)₂—, —S—S—, —N(R)—, or C—C; wherein each R is independently H or (C₁-C₆)alkyl.
 95. The polymer of claim 91 wherein a residue of the polymer is linked to a residue of the drug, through a linker.
 96. The polymer of claim 95 wherein the linker separates the residue of the polymer and the residue of the drug by about 5 angstroms to about 200 angstroms, inclusive, in length.
 97. The polymer of claim 95 wherein (1) the residue of the polymer is linked to the linker and (2) the linker is linked to the residue of the drug, independently, through an amide, ester, ether, amino, ketone, thioether, sulfinyl, sulfonyl, disulfide, or a direct linkage.
 98. The polymer of claim 95 wherein (1) the residue of the polymer is linked to the linker and (2) the linker is linked to the residue of the drug, independently, through one of the following linkages: —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—, —C(═O)—, —S—, —S(O)—, —S(O)₂—, —S—S—, —N(R)—, or C—C; wherein each R is independently H or (C₁-C₆)alkyl.
 99. The polymer of claim 95 wherein the linker is a divalent radical of the formula W-A-Q wherein A is (C₁-C₂₄)alkyl, (C₂-C₂₄)alkenyl, (C₂-C₂₄)alkynyl, (C₃-C₈)cycloalkyl, or (C₆-C₁₀)aryl, wherein W and Q are each independently —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—, —S—, —S(O)—, —S(O)₂—, —S—S—, —N(R)—, —C(═O)—, or a direct bond; wherein each R is independently H or (C₁-C₆)alkyl.
 100. The polymer of claim 95 wherein the linker is a 1,ω-divalent radical formed from a peptide or an amino acid.
 101. The polymer of claim 100 wherein the peptide comprises 2 to about 25 amino acids.
 102. The polymer of claim 100 wherein the peptide is poly-L-lysine, poly-L-glutamic acid, poly-L-aspartic acid, poly-L-histidine, poly-L-ornithine, poly-L-serine, poly-L-threonine, poly-L-tyrosine, poly-L-leucine, poly-L-lysine-L-phenylalanine, poly-L-arginine, or poly-L-lysine-L-tyrosine.
 103. The polymer of claim 91 wherein the one or more drugs are each independently: a polynucleotide, polypeptide, oligonucleotide, gene therapy agent, nucleotide analog, nucleoside analog, polynucleic acid decoy, therapeutic antibody, abciximab, anti-inflammatory agent, blood modifier, anti-platelet agent, anti-coagulation agent, immune suppressive agent, anti-neoplastic agent, anti-cancer agent, anti-cell proliferation agent, or nitric oxide releasing agent.
 104. A formulation comprising a polymer of formula (VII) as recited in any one of claims 1-27 and one or more drugs.
 105. The formulation of claim 104 wherein the one or more drugs are each independently: a polynucleotide, polypeptide, oligonucleotide, gene therapy agent, nucleotide analog, nucleoside analog, polynucleic acid decoy, therapeutic antibody, abciximab, anti-inflammatory agent, blood modifier, anti-platelet agent, anti-coagulation agent, immune suppressive agent, anti-neoplastic agent, anti-cancer agent, anti-cell proliferation agent, or nitric oxide releasing agent.
 106. A method of using a polymer as recited in any one of claims 91-102 for use as a medical device, a pharmaceutical, a carrier for covalent immobilization of a drug, or a bioactive substance.
 107. A method of using a polymer of any one of claims 91-102 for the manufacture of a medical device, a pharmaceutical, a carrier for covalent immobilization of a drug, or a bioactive substance.
 108. A polymer of formula (XI) as recited in any one of claims 46-70, that is linked to one or more drugs.
 109. The polymer of claim 108 wherein a residue of the polymer is linked directly to a residue of the drug.
 110. The polymer of claim 109 wherein the residue of the polymer is linked directly to the residue of the drug through an amide, ester, ether, amino, ketone, thioether, sulfinyl sulfonyl, disulfide, or a direct linkage.
 111. The polymer of claim 108 wherein the residue of the polymer is linked directly to the residue of the drug through one of the following linkages: —N(R)C(═O)—, —C(O)N(R)—, —OC(═O, —C(═O)O—, —O—, —C(═O)—, —S—, —S(O)—, —S(O)₂—, —S—S—, —N(R)—, or C—C; wherein each R is independently H or (C₁-C₆)alkyl.
 112. The polymer of claim 108 wherein a residue of the polymer is linked to a residue of the drug, through a linker.
 113. The polymer of claim 112 wherein the linker separates the residue of the polymer and the residue of the drug by about 5 angstroms to about 200 angstroms, inclusive, in length.
 114. The polymer of claim 112 wherein (1) the residue of the polymer is linked to the linker and (2) the linker is linked to the residue of the drug, independently, through an amide, ester, ether, amino, ketone, thioether, sulfinyl, sulfonyl, disulfide, or a direct linkage.
 115. The polymer of claim 112 wherein (1) the residue of the polymer is linked to the linker and (2) the linker is linked to the residue of the drug, independently, through one of the following linkages: —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—, —C(═O)—, —S—, —S(O)—, —S(O)₂—, —S—S—, —N(R)—, or C—C; wherein each R is independently H or (C₁-C₆)alkyl.
 116. The polymer of claim 112 wherein the linker is a divalent radical of the formula W-A-Q wherein A is (C₁-C₂₄)alkyl, (C₂-C₂₄)alkenyl, (C₂-C₂₄)alkynyl, (C₃-C₈)cycloalkyl, or (C₆-C₁₀)aryl, wherein W and Q are each independently —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—, —S—, —S(O)—, —S(O)₂—, —S—S—, —N(R)—, —C(═O), or a direct bond; wherein each R is independently H or (C₁-C₆)alkyl.
 117. The polymer of claim 112 wherein the linker is a 1,ω-divalent radical formed from a peptide or an amino acid.
 118. The polymer of claim 117 wherein the peptide comprises 2 to about 25 amino acids.
 119. The polymer of claim 117 wherein the peptide is poly-L-lysine, poly-L-glutamic acid, poly-L-aspartic acid, poly-L-histidine, poly-L-ornithine, poly-L-serine, poly-L-threonine, poly-L-tyrosine, poly-L-leucine, poly-L-lysine-L-phenylalanine, poly-L-arginine, or poly-L-lysine-L-tyrosine.
 120. The polymer of claim 108 wherein the one or more drugs are each independently: a polynucleotide, polypeptide, oligonucleotide, gene therapy agent, nucleotide analog, nucleoside analog, polynucleic acid decoy, therapeutic antibody, abciximab, anti-inflammatory agent, blood modifier, anti-platelet agent, anti-coagulation agent, immune suppressive agent, anti-neoplastic agent, anti-cancer agent, anti-cell proliferation agent, or nitric oxide releasing agent.
 121. A formulation comprising a polymer of formula (XI) as recited in any one of claims 46-70, and one or more drugs.
 122. The formulation of claim 119 wherein the one or more drugs are each independently: a polynucleotide, polypeptide, oligonucleotide, gene therapy agent, nucleotide analog, nucleoside analog, polynucleic acid decoy, therapeutic antibody, abciximab, anti-inflammatory agent, blood modifier, anti-platelet agent, anti-coagulation agent, immune suppressive agent, anti-neoplastic agent, anti-cancer agent, anti-cell proliferation agent, or nitric oxide releasing agent.
 123. A method of using a polymer of any one of claims 103-114 for use as a medical device, a pharmaceutical, a carrier for covalent immobilization of a drug, or a bioactive substance.
 124. A method of using a polymer of any one of claims 103-114 for the manufacture of a medical device, a pharmaceutical, a carrier for covalent immobilization of a drug, or a bioactive substance. 